Pharmaceutical Excipients-Boolket For Pharmacy Students

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
from this angle, the United States’
DEFINITION OF EXCIPIENT
National Formulary of 1994 states that
The term comes from the Latin word an excipient is any component other
excipients, present participle of the verb than the active principle added
excipere which means to receive, to intentionally to the medicinal
gather, to take out. This refers to one of formulation, or ‘everything in the
the properties of an excipient, which is formulation except the active drug’.
to ensure that a medicinal product has The following general criteria are essential
the weight, consistency and volume for excipients:
necessary for the correct administration of
the active principle to the patient. In 1957, • physiological inertness;
excipients were defined as ‘the substance • physical and chemical stablility;
used as a medium for giving a • conformance to regulatory agency
medicament’, that is to say with simply the requirements;
functions of an inert support of the active • no interference with drug
principle or principles. Again, in 1974 they bioavailability;
are described as ‘any more or less inert • absence of pathogenic microbial
substance added to a prescription in organisms; and
order to confer a suitable consistency or • commercially available at low cost.
form to the drug: a vehicle.
This historically somewhat limiting In reality, no single excipient would satisfy
definition referred to those substances all the criteria; therefore, a compromise of
employed in the preparation of pills, a now the different requirements has to be made.
obsolete pharmaceutical dosage form For example, although widely used in
later replaced by tablets and capsules. pharmaceutical tablet and capsule
Natural products, such as molasses and formulations as a diluent, lactose may not
honey, were long employed in the be suitable for patients who lack the
preparation of pills up to 1940 and USP intestinal enzyme lactase to break down
10 also mentioned lactose, glucose, the sugar, thus leading to the
lycopodium, glycerin and gelatin. gastrointestinal tract symptoms such as
cramps and diarrhea. The role of
To the function of simple vehicle, galenic excipients varies substantially depending
science then added that of adjuvant in the on the individual dosage form.
carrying and release of the active principle
of the formulation. Looking at the matter
ROLE OF EXCIPIENTS considered the prime reasons for including
excipients in dosage forms since they
Among these roles are to be remembered
relate directly to product performance.
those of guaranteeing the stability,
Issues such as regulatory acceptability,
precision and accuracy of the dose,
environmental effects and impact on cost
improving the organoleptic characteristics
of the product are also important selection
and the patient’s compliance. Modern
criteria.
pharmaceutical technology also requires
verification of the physical state of the
excipient, which is so important both in the Accuracy of dose
manufacturing phase and to control the Where the active ingredient is very potent
release of the active principle, with the (i.e., dose is low), it may be necessary to
object of improving the bioavailability and disperse the drug in a ‘‘diluent’’ or bulking
consequently the efficacy and tolerability of agent. Otherwise, quantities being filled
the medicinal drug. into capsules or dies for tableting may be
so low that normal filling and other process
Medicinal dosage forms, regardless of variations translate to excessive variation
composition or mode of use, must meet in unit drug content. Likewise, low-dose
the following requirements that underpin medications for inhalation as dry powders
efficacy, safety, and quality: may have the drug dispersed in or
1. Contain an accurate dose. otherwise associated with an inert ‘‘carrier’’
or flow aid. For a diluent to function in this
2. Be convenient to take or administer. way it must form a homogenous blend with
the drug. Otherwise accuracy of dose
3. Provide the drug in a form for cannot be guaranteed.
absorption or other delivery to the
target. Water may be considered a ‘‘diluent’’ in
liquid presentations as it provides the
4. Retain quality throughout the shelf life required dose in a volume that can be
and usage period. accurately dispensed or administered. It is
5. Be manufactured by a process that also invariably present in medications for
does not compromise performance and topical or transdermal application. Water
can be one of the most problematic
that is reproducible and economical.
companion materials in a dosage form
Few if any active pharmaceutical because of its capability to promote
ingredients have properties that allow hydrolysis, act as a vehicle for other
incorporation in units that meet all these molecular interactions, or simply be a
criteria. Therefore, it is necessary to add medium for microbial growth. Such
other materials to make good any properties illustrate how a material that
shortfalls. Consequently, virtually every resolves one problem may pose others
medicinal product is a combination of the that in turn require the presence of
drug substance and excipients. additional excipients.
These are indispensable components of Liquid or semisolid preparations may

medicinal products and, in most cases require the presence of ancillary excipients
comprise the greatest proportion of the to effect solvation or dispersion of the
dosage unit. It goes without saying that active ingredient. In particular, formulations
knowledge of the composition, function, containing drugs in the suspended state
and behavior of excipients is a prerequisite may require viscosity-enhancing agents or
to the successful design, development and other additives to ensure that the drug
manufacture of pharmaceutical dosage remains homogenously dispersed.
forms. Otherwise, the accuracy of the dose may
be compromised.
The requirements listed above can be
‘‘release’’ into a dosage form involves
adding a disintegrant to the tablet or
User or patient convenience capsule formulation so that on ingestion
the compact breaks up and drug is
Drugs that are bitter or otherwise released for dissolution and absorption. In
unpalatable, and administered as oral
the case of hydrophobic drugs, dissolution
liquids may be unacceptable, particularly
to younger patients. Compliance and may be aided by wetting agents. More
therefore efficacy may be compromised complex release patterns involve using
unless the product can be made more excipients to modify release from the
palatable. Thus, sweeteners, flavors, or dosage form to delay onset of action or
taste-masking agents may be present in otherwise modify the pharmacokinetics of
liquid oral products, in chewable dosage the drug, thereby maximizing efficacy or
forms, and in effervescent or dispersible minimizing side effects.
tablets that are constituted as liquids prior
to use. Excipients can influence delivery from
topical and transdermal medications. The
Some drugs given by injection cause local propensity of the drug to migrate from the
pain due to high volume, tonicity, pH, etc. formulation to the application surface is
An additive that evinces a local anesthetic affected by factors such as lipophilicity of
effect may relieve such discomfort. Benzyl the vehicle, drug solubility in the
alcohol is employed for this purpose. formulation, and
effects of additives on the barrier
properties of the skin or mucosal surface.
Release of drug from the dosage
form
Once a medication is ingested, applied to Oral absorption enhancement
a target area, or otherwise administered,
the drug must leave the dosage form for Oral absorption is indirectly aided by
absorption or other delivery to the target. excipients that promote release of drug
This may involve the following: 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
⇒ Dissolution in the gastrointestinal (GI) used. However, lipids have been used to
tract following oral dosage. enhance absorption of hydrophobic active
⇒ Partitioning to the skin in the case of ingredients. Dissolution or dispersion of
drug in such materials provides a substrate
topical or transdermal preparations.
for lipolysis, resulting in an emulsion of
⇒ Passage to pulmonary or nasal drug and lipid that provides enhanced
cavities (inhalation products). surface area for dissolution and
absorption.
Excipients can ensure that such delivery is
expeditious and consistent. Their presence Excipients that are bioadhesive or that
may be even more crucial with more swell on hydration can promote absorption
esoteric forms that must be delivered to a by increased contact with epithelial
tissue, organ, or even specific cells. surfaces, by prolonging residence time in
Researchers are developing excipients the stomach, or by delaying intestinal
that act as ‘‘homing devices’’ to guide transit. Cellulose ethers, gums of natural
drugs to designated targets. Such origin, and synthetic
approaches will be discussed later in this
chapter. In its simplest form, designing acrylic acid polymers have been evaluated
for such purposes. The range of materials
available and their differing viscoelastic EXCIPIENTS AS STABILIZERS
and rheological behaviors mean that it is
Product quality can be compromised
possible, by judicious admixture, to
during manufacture, transport, storage or
develop delivery units with balanced
use. The causes of deterioration can be
properties so that
manifold and product-specific. They
adhesion, density, hydration, drug release include microbial spoilage or chemical
rate, etc. can be tailored to the drug in transformation of the active or physical
question and the physiological changes that alter performance
characteristics of the target delivery site.
in vivo. Deterioration can compromise
safety or make the medication less
attractive, which means it may not be
Enhancers for Other Modes of used. Excipients can contribute to or cause
Absorption such changes unless carefully screened
for possible interactions in preformulation
Many physical and enzymatic barriers can
studies.
prevent successful delivery of active
pharmaceutical ingredients by non- Stablization strategies include the
invasive, non-oral routes. It is not following:
surprising, therefore, that there is great
interest in excipients that can overcome • Formulation with an excipient whose
such obstacles. Transdermal delivery is a light absorption spectrum overlaps that
case in point. The skin, particularly the of the photolabile drug. This is the so-
stratum corneum presents a formidable called spectral overlay approach.
barrier to diffusion. Materials used to
• Using an antioxidant in formulations that
enhance its permeability have ranged from
are susceptible to degradation by
simple solvents such as ethanol or
oxidation. This approach has been
propylene glycol to aromatic chemicals
particularly successful in vitamin-
such as terpenoids. Such penetration
containing products.
enhancers appear to work by disrupting
the lipid domains in the stratum corneum • Using an excipient that ‘‘hinders’’
that reduce permeability. association of groups in the same
molecule, in adjacent molecules, or in
Entry via nasal or buccal mucosa allows
the vehicle that can interact and cause
the delivery of peptides or other labile
degradation. There are several reports
drugs that are highly potent (low-dose
of cyclodextrins effecting such ‘‘steric
drugs) and that do not have steep
stabilizations.’’ Polyethylene glycol also
doseresponse relationships. Absorption
has been shown to stabilize an ointment
enhancement requires increased contact
formulation by preventing formation of
time and reduced clearance rate (in the
inactive rearrangement products.
case of nasal delivery), thereby optimizing
Equally important stabilizers include
conditions for mucosal diffusion. Excipients
preservatives in liquid products to
that enhance nasal absorption include
prevent microbial growth and buffers to
phospholipids to enhance mucosal
provide an environment conducive to
permeability and agents that imbibe water
good stability where degradation is pH-
and become mucoadhesive (e.g., glyceryl
related. Chelating agents also are used
mono oleate). In addition, the gelling
as stabilizers to prevent heavy metals
agents hydroxypropyl cellulose and
from catalyzing degradation.
polyacrylic acid promote absorption of
insulin in dogs.
EXCIPIENTS AS PROCESS AIDS
The vast majority of medicinal products are
manufactured by high-speed, largely
automated processes for reasons that are particle size) can enhance flow or act as
related as much to safety and quality as to a ‘‘carrier’’ from the dose unit (usually a
cost of goods. Excipients that aid in capsule) through the inhalation delivery
processing include the following: device to the oral cavity on inspiration.
They are widely used for these purposes
• The almost universal use of lubricants in inhalation formulations of anti-
such as stearates in tablets and asthmatic agents such as salbutamol
capsules to reduce friction between and budesonide.
moving parts during compression or
compaction.
• Excipients that aid powder flow in tablet ORIGINS AND SOURCES OF
or capsule manufacture. Materials such EXCIPIENTS
as colloidal silica improve flow from
hopper to die and aid packdown in the Excipients are of various origin:
die or capsule shell. Accuracy and 1. animal (e.g. lactose, gelatin, stearic
consistency of fill and associated dose is acid),
thereby improved.
2. plant (e.g. starches, sugars, cellulose,
• Compression aids to help form a good arginates),
compact, whether on dry granulation
(slugging) prior to tableting or on tablet 3. mineral (e.g. calcium phosphate, silica)
compression. Most are derived from and
plant, animal, or mineral origin
(microcrystalline cellulose, lactose, or 4. synthesis (e.g. PEGs, polysorbates,
magnesium carbonate). povidone, etc.)
• Agents such as human or bovine serum Their origin and use do not often
albumin that are used in the guarantee the quality required by the
manufacture of biotechnology- based pharmaceutical industry, which must
products. These avoid adsorption of the therefore submit them to more thorough
protein to flexible tubing, filters, and -going analytical controls. In order to carry
other process equipment. out the numerous functions required, new
classes of excipients have now become
• Stabilizers to protect the drug from available, derived from old and new
processing conditions that might materials, alone or in combination,
otherwise be deleterious. It is common adapted to the manufacture of high-
to use ‘‘cryoprotectants’’ such as sugars, performance pharmaceutical dosage
polyhydric alcohols or dextrans in forms.
lyophilized parenteral biotechnology
products to prevent inactivation during Looking at the matter from this angle,
freezing. excipients can no longer be considered
mere inert supports for the active
• ‘‘Flow aids’’ also can help performance principles, but essential functional
in cases where the delivery device is an components of a modern pharmaceutical
integral part of the medication. Products formulation.
for pulmonary delivery are often
formulated as dry powders that are It is also to be borne in mind that the
inhaled via the oral cavity. The fine- ratio of their weight to that of the active
particle nature of the medicinal agent, principles is usually very high in a
which may be vital for efficient delivery formulation, and such as to cause possible
to the bronchial target area, militates action due to their mass.
against good flow. Materials such as Like pharmaceutical drugs, they too
lactose or mannitol (of appropriate have their own thermo-dynamic activity
which, though generally low, can what we have said above, we may say that
contribute to reactions leading to excipients are rather more than the sugar
degradation or to interactions between the in the pill.
drug and the excipient.
At this point we may well ask ourselves
Today it is reckoned that over one what the basic requirements of a modern
thousand different materials are used in pharmaceutical excipient are. In Fig. 1 the
the pharmaceutical industry to fulfil its three essential requirements of active
various requirements such as diluents, principles are compared with those of
bulking agents, disintegrants, lubricants, excipients. Fundamental for both are
colouring agents, sweeteners, etc. quality and safety. The requirement of
therapeutic efficacy for drugs is replaced
They are chemically heterogeneous by that of functionality for excipients,
compounds that go from simple molecules defined as ‘the physical, physicochemical
(water) to complex mixtures of natural, and biopharmaceutical properties’ of the
semisynthetic or synthetic substances. same.
From the regulatory point of view, may Safety has always been the most important
be subdivided into three categories. requirement and the most studied when
1. In the first category (approved dealing with pharmaceutical drugs. Less
excipients) we find the compounds attention has been devoted to the safety of
originating from the food industry excipients, because their inertia and
(generally recognised as safe: GRAS) or innocuity were taken for granted.
that have been present in To this end, we shall examine three
pharmaceutical products for a very long issues that may compromise the safety of
time. pharmaceuticals:
2. The intermediate category (essentially (a) production, distribution and use;
new excipients) covers compounds
obtained by means of the structural (b) pharmaceutical-excipient interactions;
modification of the excipients already and
approved or those already used in the
food or cosmetic industries. (c) toxicity, which may be the cause of
frequent and sometimes notable ‘adverse
3. The third category covers new effects’.
compounds, never previously used in
the pharmaceutical field and it is
growing rapidly due to the present
DRUG–EXCIPIENT INTERACTIONS
interest in modified-release
formulations and the requirements of Excipients constitute the mass or greater
the modern high productivity volume in the usual enteral or parenteral
compressing/tabletting machines. formulations and, they often contain
reactive functional groups that may give
rise to chemical and physical
transformations. Interactions occur more
PRINCIPAL REQUIREMENTS OF
frequently between excipient and active
EXCIPIENTS principle than between excipient and
Historically, the importance of excipients in excipient and these interactions can be of
pharmaceutical formulations has two types. The physical type of interaction
generally been underestimated, as they can modify, for example, the speed of
were cheap ingredients viewed solely as dissolution or the uniformity of the dosage
inert supports for medicaments. Today, of a solid formulation. Indeed, some
this view is out-dated and, on the basis of materials can adsorb drugs to their
surfaces, thus increasing the active like a Lewis acid, giving rise to reactions
surface and consequently the wettability such as hydrolisis, epimerisation, trans -
and speed of dissolution. The contrary esterification, etc. One example is the
effect may be encountered when the hydrolisis of the imino nitrogen link of
forces of attraction are strong, in which nitrazepam with consequent disactivation
case the drug is released with difficulty and of the drug.
assimilation is compromised. One example
is that of lipophilic lubricants (e.g. However, when evaluating potential
magnesium stearate) which, when finely pharmaceutical-excipient interactions, it
dispersed on the particles of the active must however be considered that the
principle, can slow down dissolution kinetics of chemical reactions involving
and therefore bioavailability. solutions are very high, whereas in the
case of solid formulations they are low, if
The chemical type of interaction, on the not negligible.
other hand, can lead to the degradation
of the drug and/or the formation of the Despite the earlier account of excipients
so-called degradation impurities. The most acting as stabilizers, it is fair to state that
frequently encountered reaction is there are far more cases on record of
hydrolisis, because water is the preferred excipients adversely affecting quality.
and prevalent solvent in liquid Degradation may be caused by interaction
formulations. In solid forms which between functional groups in the excipient
contain hygroscopic components, the and those associated with the drug. Many
presence of humidity must be controlled small-molecule drugs contain primary,
and reduced. Even the presence of secondary, or tertiary amino groups and
oxygen, when activated by traces of these have the propensity to interact with
catalysts (heavy metal ions, light, heat. . aldehydic groups in sugars or volatile
.), may give rise to oxide-reduction and aldehydes present as residues.
the formation of free radicals (e.g. lipidic Chemical interaction can result in
peroxidation). Other, less frequent, degradation of the drug substance to
reactions are photolysis, isomerisation and inactive moieties with loss of efficacy
polymerisation, which are more likely to where degradation is excessive. Even
occur with certain types of excipients, when degradation is modest, it is possible
lowering the title of the active principle and that the formed degradation products may
generating dangerous impurities. One compromise safety.
example is the presence of polymeric
forms in beta-lactam drugs, such as Physical interactions between drug and
ampicillin, which are thought to be excipient also can compromise quality.
responsible for dangerous allergic Adsorption of drug by microcrystalline
reactions. Ionisable pharmaceuticals cellulose resulted in drug dissolution being
may react with ionised soluble excipients less than complete.
giving rise to the formation of insoluble
products due to charge interactions. In this Interaction between chloramphenicol
way, sodium alginate and neomycin cation stearate and colloidal silica during grinding
precipitate in an acqueous solution. led to polymorphic transformation.
Another type of interaction may occur Excipients may contribute to degradation

between the carbonilic groups of a widely- even when not directly interacting with
used excipient like poly-vinylpyrrolidone, active moieties. Soluble materials may
and pharmaceuticals containing donor alter pH or ionic strength, thereby
groups of hydrogen, like famotidine and accelerating hydrolytic reactions in liquid
atenolol, thus causing problems of presentations. Such effects may be
incompatibility. Even silicon dioxide accentuated during processing.
(SiO2), in anhydrous conditions, behaves
For instance, sterilization by autoclaving, Into the first category fall all the
while of short duration, may cause adverse effects proper to chemical,
significant degradation product formation natural or synthetic substances when a
because of the high temperature involved. certain dose is exceeded. The second
Dextrose is widely used in parenteral category, however, has to do with
nutrition solutions or as a tonicity modifier phenomena that are often independent
in other parenterals. Sterilization by of, or only marginally dependent on, the
autoclaving can cause isomerization to dose. That is to say, they are events linked
fructose and formation of 5-hydroxymethyl to specific characteristics of the subjects,
furfulaldehyde in electrolyte-containing such as genetically-transmitted
solutions. pathologies (metabolic illnesses, among
which phenylketonuria and lactose
At the other extremes of processing, intolerance) or genetic predisposition
succinate buffer was shown to crystallize (among which diabetes and allergic
during the freezing stage of lyophilization, pathologies).
with associated reduction of pH and
unfolding of gamma interferon. In principle, excipients ought to be
subjected to the same toxicity studies as
It is important to identify and characterize those requested for active principles, so
such ‘‘process stresses’’ during dosage- as to protect the population from
form development and tailor processing undesirable effects. This is assuredly
conditions accordingly. applicable to many compounds, especially
Microcrystalline cellulose is a partially those that are used as food additives.
depolymerized cellulose that is part- However, other substances, that have
crystalline/part non-crystalline and been used for decades now, can be
hygroscopic. Adsorbed water is not held in considered ‘safe’, given that no adverse
any ‘‘bound’’ state but will rapidly effects have been encountered in man.
equilibrate with the environment during The excipients that have been authorised
processing or storage. Thus, it is possible to be used as food additives have been
that in a dosage form, water can be evaluated as regards toxicology by the
sequestrated by a more hygroscopic active JECFA (Joint Expert Committee on Food
ingredient. If the drug is moisture sensitive, Additives), which handles the evaluation
degradation may follow. Stabilization may of the risk from consuming additives or
be possible by drying prior to use, but loss contaminants with food. In the case of
of water may make it a less effective additives, their use is voluntary and has a
compression aid. technological reason, exactly as in the
case of pharmaceutical excipients,
whereas contaminants are substances
TOXICITY OF EXCIPIENTS that can be vehicled by the food chain,
given the ubiquitousness of the distribution
A discussion of the toxicity of the of pollutants in the environment. In this
excipients employed in pharmaceutical article, our preferred source of toxicological
formulations is certainly a difficult and data has been the JECFA’s conclusions,
extremely diversified task. To simplify which take into particular consideration the
matters, the subject may be organised as results of long-term toxicological studies.
follows: The JECFA usually terminates its
• toxic effects encountered in the whole toxicological evaluations with the
population; publication of an admissible daily intake
(ADI), which represents the dose that
• toxic effects encountered only in does not carry risks to the population if
specific populations. taken every day for a life-time. This dose is
expressed in mg (or microg) per kg of daily
weight per day. To establish the total necessary. As recently as 1996, renal
daily dose, we should multiply this failure in children in Haiti was ascribed to
number by the bodily weight (usually use of glycerol contaminated with
reckoned as 60 kg). The value of the ADI diethylene glycol in a liquid paracetamol
is extrapolated from studies conducted in product. Residues in excipients can affect
laboratory animals, dividing the highest quality and performance by interacting with
dose without toxic effects in the animal by the drug or other key components.
a safety factor (generally 100). Reducing sugar impurities in mannitol were
responsible for the oxidative degradation
of a cyclic heptapeptide.
STABILITY OF EXCIPIENTS
Excipients can lose quality over time. Oils,
CONCLUSIONS
paraffins, and flavors oxidize; cellulose
gums may lose viscosity. Polymeric Medicinal products can be considered a
materials used in film coating or to modify dosed combination of two types of
release from the dosage form can age due constituents: the active principles and the
to changes in glass transition temperature. excipients. The latter are the more
This can lead to changes in elasticity, important as far as weight is concerned,
permeability, and hydration rate and whether in solid forms, suspensions or
associated changes in release properties solutions. The ideal excipient should be
or appearance. Preservatives such as able to fill numerous and important
benzoic acid or the para hydroxybenzoates functions, first among which that of
are volatile and can be lost during product guaranteeing the dose, stability and
manufacture if the process involves release of the active principle, and the
heating. patient’s ‘compliance’. Furthermore, it
should possess particular chemical,
Loss during product storage is also physical and mechanical characteristics,
feasible if containers are permeable to so as to optimise the formulation’s
passage of organic vapors. Acetate buffer ‘performance’ both during the
is volatile at low pH and can be lost during manufacturing phase (manufacturability)
the drying stages of lyophilization. Such and when used by the patient. This
behaviors reinforce the need to know the multiplicity of roles fits very ill with the
behaviors of excipients as well as of the traditional galenic view, that saw these
active ingredient so that appropriate ‘non-medicinal ingredients’ as chemically
processing, storage conditions, and ‘‘use and pharmaco-toxicologically inert.
by’’ periods are stipulated where
necessary. 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
IMPURITIES IN EXCIPIENTS
examining not only the quality and
Excipients, like drug substances contain performance but also the safety of the
process residues, degradation products or excipients. The problem is not simple if
other structural deviants formed during one considers that in countries like the
manufacture. Historically, it was not United States, Japan and Europe there are
unusual for adulterants to be added to now in use over a thousand excipients of
‘‘bulk up’’ the commodity. Thankfully, a varying origin, of more or less complex
combination of better analytical structure and belonging to different
techniques, vendor certification programs, chemical classes. About one fifth of
and quality audit systems should mean them are present in the respective
that adulteration is largely a thing of the Pharmacopoeiae, which list the
past. However, constant vigilance is pharmaceutical quality requirements but
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.
coated products and film-coated tablets is essentially the
same.
COLORING AGENTS
• Aesthetic issues in dosage form design.
DEFINITION • Identification of the product by the manufacturer and

therefore act as an aid (not a replacement) for
A material that is a dye, pigment, or other substance existing GMP procedures. Colourants also aid in the
made by a process or similar artifice, or extracted, identification of individual products by patients,
isolated, or otherwise derived with or without particularly those taking multiple medication.
intermediate or final change of identity, from a vegetable,
animal, mineral or other source and when added or • They reinforce brand imaging by a manufacturer and
applied to a food, drug, or cosmetic or to the human body thereby decrease the risk of counterfeiting.
or any part thereof, is capable (alone or through reaction
with other substances) of imparting color.
• Colourants for film-coated tablets have to a greater
or lesser extent opacifying properties which are
According to the Code of Federal Regulation of USA,
useful when it is desired to optimize the ability of the
color additives are: "Any substance, synthetic or
coating to protect the active ingredient against the
otherwise, that when added or applied to food, drug, or
action of light.
cosmetic, or to the human body or any part thereof, is
capable of imparting a color thereto".
The use of coloring agents in pharmaceutical Synthetic organic dyes and lakes
preparations for purpose of esthetics, as sensory adjunct
to the flavors employed, and for purposes of product If the water-soluble organic dye is precipitated as its
distinctiveness is important. aluminum salt on to alumina by the addition of aluminum
chloride then the pigment so formed is known as an
The need to identify tablets in order to minimize the risk aluminum salt by the addition of sodium hydroxide,
of confusion to the patient is an important factor to be bicarbonate or carbonate. The calculated quantity of dye
considered in formulation. Color provides a relatively necessary to achieve the required dye content is added
simple and convenient solution to this problem, so is to the alumina slurry and aluminum chloride solution
widely used in tablet film coating. added to effect lakeing. As soon as all the dye has been
absorbed the precipitate is washed and filtered before
Colorants commonly used can be divided into three being dry ground to the desired particle size. The
groups; pigmentary properties and the shade of the aluminum
lakes depends a great deal on the preparation of the
• the synthetic organic dyes and their respective lakes, alumina, the processing conditions during the deposition
• inorganic pigments and of the dye and the extent of grinding. The amount of dye
precipitated on the alumina is generally in the region of
• miscellaneous natural colorants. 10-40% by weight. All lakes contain approximately 15-
23% by weight residual moisture, some of which is bound
In this context the use of the world dye implies a pigment as water of hydration and all are insoluble in most
implies a material that is insoluble but disperses in the solvents.
film-coating solution.
Chemistry of color:
Definition of Terms
Before the development of synthetic color additives, food
Dyes are substances which impart color to an object; and cosmetic colorants were obtained form mineral,
soluble dyes dissolve in specified liquids. animal and vegetable sources. Synthetic coloring agents,
which were extracted from coal tar, a by-product of coal
Pigments are solid dyestuffs or mineral colors which distillation, date back to the mid-19th century. By 1900,
unfold their color effect when finely dispersed. There are nearly 700 colors had been synthesized from aniline, a
colored and white pigments. derivative of benzene produced from coal tar, and a
major industry developed in the field of coal-tar dyes.
Colorants are preparations of dyestuffs meant for Approximately 90% of color additives in prescription and
coloring. OTC drugs are synthesized from aniline that is currently
obtained from petroleum or petroleum products.
Color lakes are water-insoluble colorants obtained from
soluble, organic dyes by salt formation (e.g. with The cause of color is attributed to the presence of certain
aluminum or calcium) or surface fixation. chromophore groups within the color producing molecule.
The importance of colorants and flavoring substances is These chromophores include the
frequently undervalued, since they do not have a direct
influence on the therapeutic effect of a dosage form. -N = N- (AZO)
They do, however, enhance the acceptance of the =C=S (THIO)
product and therefore contribute substantially to a reliable -N=O (NITROSO)
therapy. Moreover, they are helpful in identifying - N = N+ - O- (AZOXY)
unpacked dosage forms. The coloring process for sugar- - N+<OO (NITRIO)
- 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 -- Dyes
-- Lakes
The light of the visual spectrum which is not absorbed by
the compound is transmitted or reflected and the -- Dyes are available in different form: Powder/ Granular/
compound assumes the color of the unabsorbed light. Plating color/ Wet dry (blends)/ Diluted (cut blends)/
Thus if a compound absorbs all light of the visible Liquid (aqueous)/ Liquid (non aqueous)/ Pests.
spectrum except that viewed by the eye as red it will
appear to be that color. -- FD&C dyes are water soluble ( and insoluble in most
organic solvents). The dyes manifested their coloring
Most of the dyes used in pharmacy, whether for their power by being dissolved in the water medium.
therapeutic or coloring properties, are salts of acid or
basic dyes. The dye ion exhibits greater resonance than -- When anhydrous conditions are of important
the parent molecule. The auxochromes are considerations, glycerin and propylene glycol are used as
capable of forming ionizable salts. Any substance solvent.
causing a decrease in the ionization will reduce the
intensity of the color. This is the basis of many -- dyes are made soluble in glycerin and then propylene
incompatibilities. 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
-- In general the certified colors can be said to be stable -- whenever possible dyes are added to
for most uses. In the dye stage no degradation has been pharmaceutical preparations in the form of dilute
noticed (other than loss in dye strength by absorbing solutions rather than as concentrated dry powders. This
moisture) in storage for 15 years. permits greater accuracy in measurement and more
consistent color production.
-- 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 -- in case of tablets, the color may be sprayed on the
good. formed tablet during the coating process,or the colorant
may be admixed as part of the dry powder mixture for
-- Two areas, in which the majority of the certified FD&C uncoated tablets.
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.
ANTIOXIDANTS
-- 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.
ANTIOXIDANTS
Safety of dyes:
Substances that reduces or inhibits oxidation of
Some examples:
chemicals and drugs in a formulation.
• Lash Lure, a coal-tar dye that was popular in 1930's for PROPERTIES:
eyebrows and eyelashes, in a few cases caused
devastating effects, such as, blindness and death. 1. Effective in low concentration.
2. adequately soluble in the product.
• FD&C Red no 2 (amaranth) caused cancer in rats, 3. non-toxic and non-irritant at the effective
reported by Russians in 1970's. In 1976, amaranth as concentration.
well as FD&C Red no 4 and Carbon black were 4. odorless, tasteless and colorless.
delisted. 5. decomposition products should be non-toxic and non
irritant.
• FD&C yellow no 5 (Tartrazine) was suspected of 6. stable and effective over a wide range of pH.
producing allergic-type reactions, including asthmatic 7. compatible with the drug and other formulation
symptoms, urticaria, angioedema, or nasal symptoms, ingredients.
especially in persons allergic to aspirin. Since 1980, 8. non volatile.
this color additive must be listed on the labels of food
and OTC drugs to alert consumers who may be Classification of Antioxidants:
sensitive to it.
A: Primary antioxidants:
Coloring technology for pharmaceuticals:
act by interfering with the propagationstep of the
-- in addition to esthetics and certification status of a autoxidtion process.
dye, a formulator must select the dyes to be used in a
particular formula on the basis of the physical and AH + R* -----> RH + A*
chemical properties of the dyes available. These include: AH + ROO* --------> ROOH + A*
solubility, pH & pKa values, pH stability, light stability
(photostable), thermal stability. Subsequently the antioxidant radical is annihilated by
combination with other antioxidant radical or some other
-- the dye must be chemically stable in the free radical.
environment of the other formulation ingredients and
must not interfere with the solubility A* + A* ------> AA
-- A colorant becomes an integral part of a A* + R* ------> AR
pharmaceutical formulation, and its exact quantitative
amount must be reproducible each time the formulation is It follwos that for effective stabilization against
prepared,or else the preparation would have a different autoxidation, the A-H chemical bond should be weaker
appearance from batch to batch. than the R-H bond of the oxidiziable substnce. However,
if the bond is too weak, then the anitoxidant will be
-- colorant generally added to liquid preparations destroyed rapidly by reaction with atmospheric oxigen.
ranges between 0.0005 to 0.001% depending upon the
colorant and the depth of color desired.
AH + O2 ----------> A* + HO2*
-- in contrast, solid dosage forms such as tablets,
capsules, sugar coated tablets, film coated tablets and
chewable tablets contain approximately 0.1% dye. It is evident that a primary antioxidant is used up by
taking part in the chain process instead of the drug.
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
- compatible with other ingredients
ANTIMICROBIAL - stable against chemical degradation
PRESERVATIVES
- solubel in common pharmaceutical vehicles
- stable in sterilizing temperature

ANTIMICROBIAL PRESERVATIVES
- capable of incativation or nutrilization for sterility testing
DEFINITION OF TERMS
- non-volatile
Disinfectants, antiseptics, and preservatives are
chemicals that have the ability to destroy or inhibit the
growth of microorganisms, and are used for this purpose. Important points:
These and other terms commonly employed are defined
as follows: * inactivation of antimicribial agens can be accmplished
using polysorbate 80 (tween 80) or lecithin.
_ Disinfectants: Chemical agents or formulations that
are too irritant or toxic on body surfaces, but are used to • Generally combinations of two gives better results
reduce the level of microorganisms from the surface of than using single preservative.
inanimate objects to one that is safe for a defined
purpose. PRESERVATIVE IDEALS
_ Antiseptics: Chemical agents or formulations that can At present there is no perfect preservative, and all
be used as an antimicrobial agents on body surfaces. materials are a compromise of a number of often contrary
properties. The following are the properties of an ideal
_ Preservatives: Chemical agents or formulations that preservative compound and need to be considered when
are capable of reducing the number of viable choosing a preservative.
microorganisms within an object or field to a level that is
safe for its designated use and will maintain the numbers 1. Definable in chemical terms: Many of the existing
of viable microorganisms at or below a level for the use/ preservatives, such as the quaternary ammonium
shelf-life of the product. compounds, are mixtures of various homologues. Often
the activity obtained is a function of the mixture
_ Bacteriostasis: A state in which the growth of composition. Unless it is possible to define and control
microorganisms is halted or inhibited. mixture composition, the performance of the agents will
be variable, even if they conform to a pharmacopoeial
_ Bactericide: A chemical antimicrobial agent that specification.
reduces the viability of a population of microorganisms
exposed to it. This term is meaningless without specifying 2. Broad spectrum of activity: The compounds must
the concentration range over which this effect is possess a broad spectrum of antimicrobial activity
obtained; such concentration ranges will vary between against all species of microorganisms and also toward
different species of microorganisms. bacterial endospores. In practice, the only compounds
that meet this requirement are formaldehyde,
_ Bacteriostat: A chemical antimicrobial agent that can gluteraldehyde, hypochlorite, and ethylene oxide. All
prevent the growth of microorganisms within an these compounds are highly irritant at sterilizing
otherwise nutritious environment. This term is concentrations to be used in pharmaceutical products.
meaningless without specifying the concentration at Formaldehyde is, however, used at low concentrations in
which this effect is achieved. Bacteriostatic some shampoos; in these cases contact with the skin is
concentrations do vary between different species of short-lived and irritancy minimal. Agents such as
microorganisms. quaternary ammonium compounds, phenolics, and the
parabens group possess good activity against gram-
It should be noted that terms such as bactericide and positive bacteria but little or no activity toward spores.
bacteriostat should be discouraged; in the USP and EP, Certain gram-negative organisms such a Pseudomonas
the term ‘‘antimicrobial agent’’ has replaced these terms. aeruginosa are virtually resistant to these agents.
Generally, antifungal activity is difficult to obtain.
Combinations of preservatives are sometimes employed
Attributes desired for antimicrobial preservatives: to widen the spectrum of activity to include molds,
bacteria, yeasts, and endospores.
- broad spectrum and non specific
3. Effectiveness: The compounds must be effective over
- continuing activity a wide range of pH in order to be effective in all
formulations. In practice, compounds are generally more
- rapid action active at either acid or alkaline pH. Thus, the pH of a
formulation determines the types of preservative suitable
- non-allergenic and non-sensitizing for inclusion.
- non toxic 4. Stablility: The compounds must be stable to light and
elevated temperatures for the expected shelf life of the
- non irritant
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
upon dilution with aqueous fluids. The biological effects
of a cosolvent that may limit or eliminate its use in drug
SOLVENT / VEHICLE formulations include their general toxicity, target organ
toxicity, tissue irritation, or tonicity with respect to biologic
membranes.
SOLVENT / VEHICLE In addition, precipitation of drug upon dilution with

aqueous media or during injection or application to
Water: mucous membranes must always be considered in
deciding if a co-solvent can be used as a vehicle for
The vast majority of injectable products and oral liquid poorly water-soluble drugs.
formulations are aqueous solutions because of the
physiological compatibility of water with body tissues. When used as a method for increasing the chemical
Additionally, the high dielectric constant of water makes it stability of a drug, cosolvents may be effective by one or
possible to dissolve ionizable electrolytes, and its two mechanisms. If a drug is susceptible to hydrolytic
hydrogen-bonding potential facili-tates the solution of degradation, cosolvents may reduce the degradation of
alcohols, aldehydes, ketones, and amines. the drug by substituting for some or all of the water in the
formulation. Alternatively, a cosolvent may enhance the
The current USP has monographs for stability of a drug by providing a less suitable
environment for the transition state of the reactants,
1. Purified Water, provided the transition state is more polar than the
2. Water for Injec-tion (WFI), reactants themselves.
3. Sterile WFI,
4. Bacteriostatic WFI, and A non-aqueous solvent must be selected with great care
5. Sterile Water for Irrigation. for it must not be irritating, toxic, or sensitizing, and it
must not exert an adverse effect on the ingredients of the
Water Miscible Vehicles: (Non-aqueous Solvents) formulation.
Cosolvents are defined as water-miscible organic Solvents that are miscible with water, and that are usually
solvents that are used in liquid drug formulations to used in combination with water as the vehicle, include
• increase the solubility of poorly water-soluble 1. Dioxolanes,

substances or to 2. Dimethylacetamide,
• enhance the chemical stability of a drug. 3. N-q3-hydroxyethyl)-lactamide,
4. Butylene glycol,
Cosolvency, then, refers to the technique of using 5. Polyethylene glycol 400 and 600,
cosolvents for the stated purposes; it is also commonly 6. Propylene glycol,
referred to as solvent blending. Cosolvency has been 7. Glycerin, and
used as an approach for preparing liquid drug 8. Ethyl alcohol.
preparations throughout the history of drug formulation.
Certain drugs of botanic origin were known to be poorly The most frequently used nonaqueous solvents are
soluble in water and required formulation in water– polyethylene glycol, propylene glycol, and fixed oils.
ethanol mixtures in order to deliver an adequate dose of These solvents have been reviewed elsewhere and the
drug in a small volume of preparation. reader is referred to this review for further details.
A common example of a class of formulation containing Non-aqueous Vehicles:

cosolvents is the elixir, which by definition is a
sweetened, hydroalcoholic solution intended for oral use. Drugs that are insoluble in aqueous systems are often
Tinctures, which generally contain even higher amounts incor-porated in metabolizable oils. Steroids, hormones,
of alcohol, are another classic example of a liquid dosage and vitamins are incorporated in vegetable oils such as
form containing a cosolvent. The need to employ peanut, sesame, corn, olive, and cottonseed. Oil
cosolvents in the formulation of new drugs as solutions injections are only administered intramuscularly. There
for oral, parenteral, and topical use remains high, are strict speci-fications for the vegetable oils used in
especially with the increasing structural complexity of manufacturing intramuscular injections. Storage of these
new therapeutic agents. preparations is important if stability is to be maintained.
For example, they should not be subjected to conditions
In many cases, cosolvency can increase the solubility of above room tempera-ture for extended periods of time.
a non-polar drug up to several orders of magnitude Although the oils used for injections are of vegetable
above the aqueous solubility. This would be significant, origin, federal regulations require that the specific oil be
for example, in a formulation problem where it might be listed on the label of a product, because some patients
necessary to increase the solubility of a drug 500-fold or have exhibited allergic re-sponses to certain vegetable
more. The use of cosolvents to prepare solution oils.
formulations of non-polar drugs is a simple and
potentially effective way to achieve high concentrations of Water-immiscible solvents include
drug. 1. Fixed oils,
2. Ethyl oleate,
The primary disadvantages of cosolvency include the 3. Isopropyl myristate, and
potential for biological effects and the potential for drugs 4. Benzyl benzoate.
that have been solubilized using cosolvents to precipitate
alkylbenzyl dimethyl ammonium Chlorides.
SURFACTANTS IN 3. Ampholytic surfactants (also called zwitterionic
PHARMACEUTICAL surfactants), where the molecule contains, or can
potentially contain, both a negative and a positive charge,
PRODUCTS (e.g., the sulfobetaines). Examples of pharmaceutical
importance include N-Dodecyl-N,
N-Dimethylbetaine.
Surfactants in Pharmaceutical Products
4. Nonionic surfactants, where the hydrophile carries
Surface-active agents (surfactants) are substances no charge but derives its water solubility from highly polar
which, at low concentrations, adsorb onto the surfaces or groups such as hydroxyl or polyoxyethylene
interfaces of a system and alter the surface or interfacial (OCH2CH2O–) groups. Examples of pharmaceutical
free energy and the surface or interfacial tension. importance include polyoxy ethylated glycolmonoethers
(e.g., cetomacrogol), sorbitan esters (Spans) and
Surface-active agents have a characteristic structure, polysorbates (Tweens).
possessing both polar (hydrophilic) and non-polar
(hydrophobic) regions in the same molecule. Thus Applicatons of surfactants
surfactants are said to be amphipathic in nature.
• Liquid dosage forms- solubilizers for poorly soluble
drugs-Miceller solubilization
Surfactant classification
• Suspensions- wettening agents for hydrophobic
Surfactant molecules may be classified based on the drugs
nature of the hydrophilic group within the molecule. The • Emulsions- emulsifying agents, Micro-emulsions
four main groups of surfactants are defined as follows:
• Topical ointment- as base, improve spreading.
1. Anionic surfactants, where the hydrophilic group • Solid dosage forms- solubility enhancement or
carries a negative charge, such as carboxyl (RCOO_), dissolution improvement of poorly soluble drugs
sulphonate (RSO3_) or sulphate (ROSO3_). Examples of
pharmaceutical importance include potassium laurate, • Tablet coating- improvement of coating solution
and sodium lauryl sulphate. spredability
• Drug delivery- Lyposome, Niosomes.
2. Cationic surfactants, where the hydrophilic group
carries a positive charge (e.g., quaternary ammonium • Preservatives- some cationinc surfactants act as
halide. Examples of pharmaceutical importance include preservative.
cetrimide, a mixture consisting mainly of tetradecyl, • Aerosols– wetting agents
dodecyl and hexa decyl trimethyl ammonium bromides,
as well as benzalkonium chloride, a mixture of
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.
>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
Major application of polymers in current pharmaceutical
POLYMERS 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
A monomer is a small molecule that combines with other implants and are expected to perform longterm service.
molecules of the same or different types to form a This requires that the polymers have unique properties
polymer. Since drawing a complete structure of a that are not offered by polymers intended for general
polymer is almost impossible, the structure of a polymer applications. Table 20–3 provides a list of polymers with
is displayed by showing the repeating unit (the monomer their applications in pharmaceutical and biomedical
residue) and an “n” number that shows how many industries.
monomers are participating in the reaction.
In general, the desirable polymer properties in
From the structural prospective, monomers are generally pharmaceutical applications are film forming (coating),
classified as olefinic (containing double bond) and thickening (rheology modifier), gelling (controlled
functional (containing reactive functional groups) for release), adhesion (binding), pH-dependent solubility
which different polymerization methods are utilized. If (controlled release), solubility in organic solvents (taste
two, three, four, or five monomers are attached to each masking), and barrier properties (protection and
other, the product is known as a dimer, trimer, tetramer, packaging).
or pentamer, respectively. An oligomer contains from 30
to 100 monomeric units. Products containing more than From the solubility standpoint, pharmaceutical polymers
200 monomers are simply called a polymer (Fig. 20–1). can be classified as water-soluble and water-insoluble
(oilsoluble or organic soluble). The cellulose ethers with
In a traditional pharmaceutics area, such as tablet methyl and hydroxypropyl substitutions are water-soluble,
manufacturing, polymers are used as tablet binders to whereas ethyl cellulose and a group of cellulose esters
bind the excipients of the tablet. Modern or advanced such as cellulose acetate butyrate or phthalate are
pharmaceutical dosage forms utilize polymers for drug organic soluble. Hydrocolloid gums are also used when
protection, taste masking, controlled release of a given solubility in water is desirable.
drug, targeted delivery, increase drug bioavailability, and
so on and so forth. The synthetic water-soluble polymers have also found
extensive applications in pharmaceutical industries,
Apart from solid dosage forms, polymers have found among them polyethylene glycol, polyethylene glycol
application in liquid dosage forms as rheology modifiers. vinyl alcohol polymers, polyethylene oxide, polyvinyl
They are used to control the viscosity of an aqueous pyrrolidone, and polyacrylate or polymethacrylate esters
solution or to stabilize suspensions or even for the containing anionic and cationic functionalities are well-
granulation step in preparation of solid dosage forms. established.
CLASSIFICATION OF FLAVORING AGENTS
FLAVORS AND
Natural flavouring substances: Natural flavouring
FLAVOR MODIFIERS substances means flavouring substances obtained from
plant or animal raw materials, by physical, microbiological
or enzymatic processes. They can be either used in their
Flavors and Flavor Modifiers natural state or processed for human consumption, but
cannot contain any nature-identical or artificial flavouring
The use of flavors and flavor modifiers to improve the substances.
taste and aroma of foods and pharmaceuticals is an art
that dates back several centuries. In large measure, the Nature-identical flavouring substances: Nature-
practice is still the same today and, except for the advent identical substances means flavouring substances that
of new semi-synthetic flavoring agents with improved are obtained by synthesis or isolated through chemical
stability, the field has remained relatively unchanged. In processes, which are chemically identical to flavouring
the analytical arena, the story is different. substances naturally present in products intended for
human consumption. They cannot contain any artificial
DEFINITION OF FLAVOR flavouring substances.
The sensory perceptions are both qualitative as well as Artificial flavouring substances: Artificial flavouring
quantitative and, therefore, can be measured. Webster’s substances means flavouring substances not identified in
New Collegiate Dictionary defines flavor as the ‘‘ . . . a natural product intended for human consumption,
quality of something that affects the sense of taste, . . . whether or not the product is processed.
the blend of taste and smell sensations evoked by a
substance in the mouth.’’ This definition is correct, but TASTE
incomplete, and should be redefined to include feeling
factors. The four primary taste- Sweet, bitter, sour and saline-
appea4r to be the result of partly of physicochemical and
1. “Flavor is the sensation produced by a material partly of psychological action.
taken in the mouth, perceived principally by the
senses of taste and smell, and also by the Taste partly depends on the ions which are produced in
general pain, tactile, and temperature receptors the mouth, but psychologists have demonstrated that
in the mouth. Flavor also denotes the sum of the sight (color) and sound also play a definite role when
characteristics of the material which produces certain reflexes become conditioned through custom and
that sensation.” association of sense perceptions. Thus, in the classic
2. Flavor is the complex effect of three experiments of Pavlov demonstrating "conditiond
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.”
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

PREPARATIONS
The odor component of flavor is due to conscious or
subconscious reactions to volatile substances, without A number of criteria are used to select flavors during
which most foods would be lacking in taste appeal. By formulation. Different flavor concentrations produce
closing the nostrils while eating a mouthful of some highly subjective sensations. Specific requirements for
flavored substance and immediately following this with balance and fullness are dependent, in part, on the drug
another mouthful with the nostrils open, it may be shown substance and the physical form of the product.
that food could be rendered tasteless, as is often
experienced by people suffering from the effects of a For this reason, when selecting a flavor system, the
compounding pharmacist must take into account several countries xylitol, cyclamate and the herbal
variables upon which a desired response would depend. sweetener stevia are used extensively.
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 Flavor Enhancers and Potentiators
specific examples to consider are:
Flavor enhancers are used universally in the food and
_ Immediate flavor identity from the formulation as it is pharmaceutical industries. Sugar, carboxylic acids (e.g.,
ingested. citric, malic, and tartaric), common salt (NaCl), amino
acids, some amino acid derivatives (e.g., monosodium
_ Compatible mouth feel factors and rapid development glutamate—MSG), and spices (e.g., peppers) are most
of a fully blended flavor in the mouth during ingestion of often employed. Although extremely effective with
the product. proteins and vegetables, MSG has limited use in
pharmaceuticals because it is not a sweetener. Citric acid
_ Absence of ‘‘off’’ notes in the mouth and a mild is most frequently used to enhance taste performance of
transient aftertaste during ingestion of the product. both liquid and solid pharmaceutical products, as well as
a variety of foods. Other acidic agents, such as malic and
The selection of a flavor system, thus, requires an tartaric acids, are also used for flavor enhancement. In
extensive evaluation of a number of organoleptic oral liquids, these acids contribute unique and complex
qualities. Vehicle components within which the drug is organoleptic effects, increasing overall flavor quality.
presented have a significant bearing on the performance Common salt provides similar effects at its taste
of the flavor system. Of these, the sweetener is perhaps threshold level in liquid pharmaceuticals. Vanilla, for
the most relevant. example, has a delicate bland flavor, which is effectively
enhanced by salt.
Sweeteners
Taste-Masking Agents
The most commonly used sweeteners are sucrose,
glucose, fructose, sorbitol, and glycerin. Using sucrose The flavoring industry has many proprietary products
(sugar) as a standard, with 100 units of sweetness, Table purported to have excellent taste-masking properties,
6 lists the relative intensities of other sweeteners. which have been used with some success. Yet, there are
a number of natural and artificial flavors that can be
Glycerin, glucose, sorbitol, and sucrose have limited use generally described to possess similar taste-masking
in solid dosage forms (e.g., tablets) because the effects. Of the many tastes that must be masked in
materials are hygroscopic. Mannitol is used more often in pharmaceuticals, bitterness is most often encountered; to
tablet manufacture. Besides being less hygroscopic, it mask it completely is difficult. A tropical fruit has been
has a negative heat of solution. For this reason, used for centuries in central Africa to mask the bitter
chewable tablets containing mannitol have a pleasant taste of native beers. This so-called ‘‘miracle berry’’
cooling sweet taste, which complements flavor quality. contains a glycoprotein that transiently and selectively
The artificial sweetener saccharin is widely used in foods binds to bitter taste buds. Due to stability challenges,
and pharmaceuticals. It is approximately 350_ as sweet attempts to isolate the compound for commercial
as sugar. It is sweet at very low concentrations exploitation have been unsuccessful. Yet, many fruit
(equivalent to about 5–10% sugar) but bitter at higher syrups are relatively stable in pharmaceuticals if
concentrations. formulated with antimicrobial preservative agents. Syrups
of cinnamon, orange, citric acid, cherry, cocoa, wild
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.
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
cherry, raspberry, or glycyrrhiza elixir can be used to aromatic elixir, orange, and wild cherry. Sour and metallic
effectively mask salty and bitter tastes in a number of tastes in pharmaceuticals also can be reasonably
drug products. The extent to which taste-masking may be masked. Sour substances containing hydrochloric acid
achieved is not usually predictable due to complex are most effectively neutralized with raspberry and other
interactions of other flavor elements in these products. fruit syrups. Metallic tastes in oral liquid products (e.g.,
iron) are usually masked by extracts of gurana, a tropical
The degree to which bitterness may be masked by these fruit. Gurana flavor is used at concentrations ranging
agents ranks in a descending order: cocoa syrup is from 0.001 to about 0.5% and may be useful in solid
most effective, followed by raspberry syrup, cherry, products as well (e.g., chewable tablets and granules).
cinnamon, compound sarsaparilla, citric acid, licorice,
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
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
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
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
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

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Pharmaceutical Excipients-Boolket For Pharmacy Students

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PHARMACEUTICAL

Prof. Reza-ul Jalil

⇒ MAJOR GROUPS OF EXCIPIENTS USED IN DOSAGE FORMS

⇒ FLAVORS AND FLAVOR MODIFIERS

These are indispensable components of Liquid or semisolid preparations may

Another type of interaction may occur Excipients may contribute to degradation

MAJOR GROUPS OF EXCIPIENTS USED IN DOSAGE FORMS

Acidifying agent Carriers for dry powder inhalers

Adhesive agent Solvents

Alkalizing agent Suppository bases

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.

DEFINITION • Identification of the product by the manufacturer and

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

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

Synthetic -- Good coloring technology recommends that the dyes

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

-- The azo triphenyl methane dyes are easily reduced to

Nitrogen containing substance

Sulphur containing substances

Potasium and sodium

Other examples are:

- stable in sterilizing temperature

SOLVENT / VEHICLE In addition, precipitation of drug upon dilution with

• increase the solubility of poorly water-soluble 1. Dioxolanes,

A common example of a class of formulation containing Non-aqueous Vehicles:

1. The buffer must have adequate capacity in the desired

Buffers in pharmaceutical systems

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

In addition, preformulation scientists routinely use buffer

It is worth noting that some of these tableting excipients

Odor: FLAVOR SELECTION IN PHARMACEUTICAL

List of sugar substitutes

Natural sugar substitutes

Artificial sugar substitutes

Glucin — 300× sweetness (by weight)

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

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