PHARMACEUTICAL EXCIPIENTS

Excipients – an overview

• Drug products contain both drug substance (commonly

referred to as active pharmaceutical ingredient or API)
and excipients.
• The resultant biological, chemical and physical
properties of the drug product are directly affected by
the excipients chosen, their concentration and
interactions with the API:
– Consistency of drug release and bioavailability
– Stability including protection from degradation
– Ease of administration
• Excipients are sub-divided into various functional
classifications, depending on the role that they are
intended to play in the resultant formulation.
• Certain excipients can have different functional roles
in different formulation types,
• e.g. lactose; widely used as:
• a diluent, filler or bulking agent in tablets and
capsules
• a carrier for dry powder inhalation products.
• In addition, individual excipients can have different
grades, types and sources depending on those
different functional roles….
 API (Active Pharmaceutical Ingredients)
• Active Pharmaceutical Ingredients (API) (or) Drugs
(meant for oral administration) are classified into two
types based on their solubility:
• a) Insoluble drugs.
• b) Soluble drugs.
• a)Insoluble drugs : The therapeutic action of
insoluble drugs ( seen locally in GI tract, Eg: Antacids
and adsorbents) depends on the surface properties
of the drug particles i.e., fine particle size and larger
surface area.
 API (Active Pharmaceutical Ingredients)

• The bioavailability of these drugs in GIT along with its

optimal surface is affected by :
( I ) Formulation (composition ) of the tablet.
(II) Granulation method (dry granulation or wet
granulation).
(III) Method of tabletting (compression or compaction).
API (Active Pharmaceutical Ingredients)

b) Soluble drugs : The therapeutic action of soluble

drug is seen systemically. The disintegration and
dissolution time of such tablets depends upon the
excipients used in the formulation. Solubility of the
drug should be considered at or above the
absorption site (i.e., upper GIT or the intestinal tract).
 API (Active Pharmaceutical Ingredients)

• The physical and chemical properties of the drugs

must be studied extensively before finalising the
tablet formula so as to obtain better tabletting
characteristics. Active pharmaceutical ingredient
(API), therapeutic agent Should not produce any
toxic effect when it comes in contact with other
additives, Should be of accurate quantity as label
claim, Should be detected by various methods of
analysis. Example: paracetamol, aspirin, diclofenac,
metformin,telmisartan, nimesulide , nifedipine etc.
 Diluents
• Diluents : Act as fillers used to make required bulk of
the tablet. Diluents are used to increase the bulk
content of the dosage form, this is done in a situation
where the active constituent to be incorporated in
the formulation is of less quantity.
• For e.g. if the active ingredient is just 5 mg, is such a
case a tablet of just 5 mg is very difficult to compress,
manufacture and handle too, thus the bulk content is
increased by addition of inactive excipient. Must
provide better tablet properties such as improved
cohesion, to permit the use of direct compression
manufacturing or to promote flow.
Diluents
A diluent should have following properties:
• Non toxic.
• Commercially available in acceptable grade.
• Low in cost. Physiologically inert.
• Physically & chemically stable by themselves & in
combination with the drugs.
• Free from all microbial contamination.
• Should not alter the bioavailability of the drug .
• Color compatible.
Commonly used tablet diluents
• Diluents Based on Chemical nature Solubility Organic diluents
Inorganic diluents Water soluble diluents Water Insoluble
diluents. For e.g.
• Lactose-anhydrous and spray dried lactose
• Directly compressed starch- Sta Rx 1500
• Hydrolyzed starch-Emdex and Celutab
• Microcrystalline cellulose-Avicel (PH 101 and PH 102)
• Dibasic calcium phosphate dehydrate
• Calcium sulphate dihydrate
• Mannitol
• Sorbitol
• Sucrose- Sugartab, DiPac, Nutab
 Characteristics of Diluents
• Most of the excipients are dehydrates,i.e. contain
certain amount of bound water, this bound water is
important during granulation process, it reduces the
hygroscopic nature of the formulation making the
formulation stable.
• For the active ingredients which are sensitive to
water anhydrous excipients like anhydrous lactose or
anhydrous dibasic calcium phosphate are used .
• Spray dried lactose, direct compressible starch and
MCC (avicel) are the diluents that can be used when
the formulation is prepared by direct compression.
 Characteristics of Diluents
• Mannitol is one of the costliest diluents but it is
still used due to the refreshing sensation given by
it when it is used in the chewable tablets.
• Sucrose or sugar based diluents are used for
direct compression formulations. Sucrose based
diluents include: Sugartab (90-93% sucrose + 7 to
10%invert sugar), Dipac (97% sucrose + 3%
modified dextrin) and Nutab( 95%sucrose+4%
invert sugar with small amount of corn starch and
magnesium stearate)
 Binders /Adhesives
• These are the dry powders or liquid which are added
during wet granulation to promote granules or to
promote cohesive compact during direct
compression.
• It provides mechanical strength to the tablet. Binders
can be in powder form and liquid form.
• Example of binders are:
– Powder binders : cellulose, methyl cellulose,
polyvinyl pyrrolidine,
– Solution binders : gelatine, PVP, HPMC, PEG,
sucrose, starch
Binders
• Binders can be added in the following ways to the
formulation added as powder before wet
agglomerisation so that the binder is evenly
distributed. As solution form it is used as
agglomerisation liquid in the wet granulation. It is
called as liquid binder.
 Binders
• As a dry powder, which is mixed with other
ingredients before compaction (slugging or
tabletting). It is called as dry binder.
• Natural binders like acacia and tragacanth are used in
solution form in the concentration of 10-25%, alone
(or) in combination for wet granulation and they can
be added as powder for the direct compression
process.
• Gelatine is used along with acacia (or) alone this
form a better binding agent than the above two
natural polymers.
Binders
• Polymers like Methyl cellulose (MC), HPMC (Hydroxy
Propyl Methyl cellulose) are used as dry powders in
case of direct compaction, they act as good binding
agents, in the solution form they act as good
adhesives.
• Ethyl cellulose and HPMC can be used in alcoholic
solutions, they act as anhydrous adhesives.
Disintegrants
• Disintegrants are added to the formulation as it breaks the
dosage form into smaller particles when it comes in
contact with the liquid, these smaller fragments have
greater surface area which will increase the dissolution of
the drug.
• Various mechanism of disintegrations are proposed-
– By breaking into fragments: When the tablet comes in
contact with the liquid, the liquid penetrates into the
pores of the tablets and breaks it into fragments. To
improve the water uptake into the pores certain
hydrophilic polymers are added to the formulation.
– By swelling: when the tablet comes in contact with the
water it swells and ruptures the tablet into small
particles.
Disintegrants
• Examples of disintegrants are:
starch, starch derivatives, clay, cellulose, alginates, PVP
(Polyvinyl pyrolidone), cross linked Na CMC (carboxy
methyl cellulose). Starch is used for in the concentration
range of 5 to 20% of the tablet weight. Modified starch
are also used which like Primogel, Explotab. These are
used in the low concentration like 1 to 8%, Pregelatinised
starch is also employed in the formulation with 5%
concentration. Clay like Veegum HV and Bentonite are
used in 10% level, Polymers like cross linked PVP, CMC are
also used as disintegrants.
 Superdisintegrants
• As day’s pass, demand for faster disintegrating
formulation is increased. So, pharmacist needs to
formulate disintegrants i.e. Superdisintegrants which
are effective at low concentration and have greater
disintegrating efficiency and they are more effective
intragranularly.
Superdisintegrants
• But, they have one drawback i.e., they are hygroscopic.
Therefore, they not used with moisture sensitive drugs.
And this superdisintegrants act by swelling and due to
swelling pressure exerted in the outer direction or
radial direction, it causes tablet to burst or the
accelerated absorption of water leading to an
enormous increase in the volume of granules to
promote disintegration.
• Examples are Crosscarmellose ,Ac-Di- Sol, Nymce ZSX,
Primellose, Solutab, Vivasol Cross linked cellulose -
Swells 4-8 folds in < 10 seconds. -Swelling and wicking
both.
 Swells in two dimensions.
Superdisintegrants
• Starch free Crosspovidone, Crosspovidone M, Kollidon
Cross linked PVP
 Swells very little and returns to original size after
compression but act by capillary action.
• Water insoluble and spongy in nature so get porous
tablet. Sodium starch glycolate Explotab, Primogel
Crosslinked starch -Swells 7-12 folds in <30 seconds.
• Swells in three dimensions and high level serve as
sustain release matrix Alginic acid NF Satialgine
Crosslinked alginic acid.
 Rapid swelling in aqueous medium or wicking action -
Promote disintegration in both dry or wet granulation.
 Lubricants
• Lubricants: Lubricants are used to reduce the friction
between the tablet and die cavity when the tablet is
getting ejected from the die cavity. Lack of lubricant
can lead to problems like capping, scratch on the
sides of the tablet, fragmentation of the tablet,
shape out etc.
• Thus to avoid this lubricants are to be used.
Lubricants
• For a lubricant the time of addition, concentration
in which it is to be added and the combination are
the important parameters.
• Concentration: as most of the lubricants are
hydrophobic in nature thus the an increased
concentration of lubricant would lead to problems
like poor wettability, and dissolution and
disintegration problem. For this reason they are
added in the concentration less than 1%.
 Lubricants
• Time of mixing: It is important as overmixing may
lead to reduction in tablet dissolution and
disintegration. Combination: If the lubricant is mixed
with the disintegrant it will lead to formation of an
film of lubricant on the tablet surface which will
reduce the disintegration.
• Examples of lubricants are: stearic acid, stearic acid
salt, stearic acid derivatives, talc, PEG, surfactants,
waxes ,etc. Calcium stearate and magnesium stearate
(0.25–0.50%w/w) are the most commonly used
lubricants followed by talc.
• Higher molecular weight poly ethylene glycol and
certain polymeric surfactants are used as water
soluble lubricants.
 Lubricants
• Lubrication can be achieved by two ways-
– Fluid lubrication: it is achieved by the addition of
liquid paraffin which forms an liquid film over the
surface, but this is rarely followed.
– Boundary lubrication: in this powder is mixed to
the formulation which forms a film on the surface
which reduces the friction.
Lubricants
• Lubricants can be of two types:
1. Insoluble lubricants: these are added to the
formulation at the end before the compression of
the tablet.
• Examples include: magnesium stearate, stearic acid,
glyceryl palmito stearate, etc.
2. Soluble lubricants: these are added to overcome the
defects caused by the insoluble lubricants.
• Examples include: PEG, poly oxy ethylene stearate,
lauryl sulphate salt, etc.
 Glidant
• Glidants are used to improve the flow property of the
formulation, it reduces the friction between the particles
and between the hopper and particles and die cavity and
particles.
• Actually glidant, lubricant and antiadherent have a close
relation to each other. They have some functions in
common.
• Most of the glidants used are hydrophobic thus they are
to be carefully added i.e. concentration regulated.
• Examples of glidants are talc, colloidal silicone dioxide
(Aerosil) , corn starch. Glidants should be of small size so
that they can retain with in the small pores of the
granules that have a greater surface area.
Coating Agent:
Coating is a process by which an essentially dry, outer
layer of coating material is applied to the surface of a
dosage form and agents which are used in this coating
process is called coating agents.
Types:
Three types of coating agents are used pharmaceutically,
Film coating.
Sugar coating.
Compression coating.
Coating Agent:
• Function of coating agents:
 Protection,
 masking,
 elegance,
 ease of swallowing,
 identification etc..
• Examples: HPMC, MC, HPC etc.
Excipients For Suspension Products
• Again, excipients are sub-divided into various functional
classifications, depending on the role that they play in the resultant
formulation.
• In Liquid/Suspension products, the possible types of excipients
include:
 Solvents/co-solvents e.g. Aqueous Vehicle, Propylene Glycol, Glycerol
 Buffering agents, e.g. Citrate, Gluconates, Lactates
 Preservatives, e.g. Na Benzoate, Parabens (Me, Pr and Bu), BKC
 Anti-oxidants, e.g. BHT, BHA, Ascorbic acid
 Wetting agents, e.g. Polysorbates, Sorbitan esters
 Anti-foaming agents, e.g. Simethicone
 Thickening agents, e.g. Methylcellulose or Hydroxyethylcellulose
 Sweetening agents, e.g. Sorbitol, Saccharin, Aspartame, Acesulfame
 Flavouring agents, e.g. Peppermint, Lemon oils, Butterscotch, etc.
Humectants, e.g. Propylene Glycol, Glycerol, Sorbitol
 Solvents/Co-Solvents
• Water is the solvent most widely used as a vehicle
due to:
– Lack of toxicity, physiological compatibility, and
good solubilising power (high dielectric constant),
but
• Likely to cause instability of hydrolytically
unstable drugs
• Good vehicle for microbial growth
• Sorbitol, dextrose, etc. are often added as
solubilisers, as well as base sweeteners
– Similar pros and cons to water alone
Solvents/Co-Solvents
• Water-miscible co-solvents are used to:
 Enhance solubility, taste, anti-microbial effectiveness or
stability
 Reduce dose volume (e.g. oral, injections)
 Or, conversely, optimise insolubility (if taste of API is an
issue)
• Examples: propylene glycol, glycerol, ethanol, low
molecular weight PEGs
• Water-immiscible co-solvents,
• e.g. Emulsions / microemulsions using fractionated coconut
oils
Buffering agent
These are materials which, when dissolved in solvent will
enable the solution to resist any change in pH should an
acid or an alkali be added. The choice of suitable buffer
depends on the pH and buffering capacity required.

Features of buffering agent

It should have a low toxicity, it should be buffered at the
range of 7.4 as the pH of the body is 7.4, it should be
non-irritant.

Examples of buffering agent

Most of the buffering system are based on carbonate,
citrates, gluconates ,lactates, phosphates, or tartrates etc.
 Preservatives
• Preservatives used in multi-use
cosmetic/pharmaceutical products (including paediatric
formulations)
– prevents an increased risk of contamination by
opportunistic microbial pathogens (from excipients or
introduced externally), resulting in potential health
consequences
• Ideally targeted for microbial cells - showing no
toxicity/irritancy towards mammalian cells
– In reality, the majority of effective GRAS preservatives
are active against both microbial and mammalian cells
(non-specific cytoplasmic poisons)
Preservatives
• There is a limited number of approved preservatives
available for multi-use oral products, and options are
even more limited for other routes of administration.
• This restricted number can be further reduced by
dose, pH-solubility profiles, incompatibilities,
adsorption, toxicity and other relevant physico-
chemical factors.
Preservatives:
Preservatives are substances that commonly added to
various foods and pharmaceutical products in order to
prolong their shelf life.
Ideal properties of preservatives:
In concept, the preservative system protects the product
against microbial proliferation but does not compromise
product performance.
Preservatives
• In practice, this means that it must:
 Exert a wide spectrum of antimicrobial activity at low
inclusion levels.
 Maintain activity throughout product manufacture, shelf
life and usage.
 Not compromise the quality or performance of product,
pack or delivery system.
 Not adversely affect patient safety or tolerance of the
product.
• Examples: Methyl & Ethyl parabens, Propyl paraben,
Benzoic acid and its salts, Sorbic acid and its salts.
Antioxidant:
An antioxidant is a molecule that inhibits the oxidation of
other molecules. Oxidation is a chemical reaction that
transfers electrons or hydrogen from a substance to an
oxidizing agent.

Ideal Properties of Antioxidants:

Effective at a low, nontoxic concentration
Stable and effective under normal conditions of use,
over a wide pH and temperature range
Soluble at the required concentration
Compatible with a wide variety of drugs and
pharmaceutical excipients
Free from objectionable odor, objectionable taste
 Colorless in both the original and oxidized form
 Nontoxic both internally and externally at the
required concentration
 Reasonable cost
 Unreactive (does not adsorb, penetrate, or
interact) with containers or closures
• Examples: BHT( Butylated Hydroxy Toluene),
BHA( Butylated Hydroxy Anisol), Sodium sulfite,
Ascorbic acid etc.
 Anti-Oxidants

• Used to control oxidation of:

– API, e.g. lovastatin
– Preservative, e.g. potassium sorbate
– Vehicle, e.g. oils or fats susceptible to β-oxidation
• Sacrificial (more oxidisable than API, preservative, etc).
Levels will reduce with time…. need to be monitored by
specific assay
• Need to assess regulatory acceptability (differs in
different countries)
Anti-oxidants
• Efficacy can be affected by:
Compatibility with other excipients
Partitioning into micelles (from surfactants)
Adsorption onto surfaces (container,
thickening agent and suspended particles)
Incompatibilities, e.g. with metal ions
 Wetting Agents
• To aid ‘wetting’ and dispersion of a hydrophobic
API, preservative or antioxidant
– Reduce interfacial tension between solid and
liquid during manufacture or reconstitution of a
suspension
– Not all are suitable for oral administration
• Examples include:
 Surface active agents, e.g.
 Oral: polysorbates (Tweens), sorbitan esters (Spans)
 Parenteral: polysorbates, poloxamers, lecithin
 External: sodium lauryl sulphate
• ….but these can cause excessive foaming (see anti-foaming
agents) and can lead to deflocculation and undesirable
physical instability (sedimentation) if levels too high
Hydrophilic colloids that coat hydrophobic particles, e.g.
bentonite, tragacanth, alginates, cellulose derivatives.
Also used as suspending agents, these can encourage
deflocculation if levels are too low.
 Anti-Foaming Agents

• The formation of foams during manufacturing processes

or when reconstituting liquid dosage forms can be
undesirable and disruptive.
• Anti-foaming agents are effective at discouraging the
formation of stable foams by lowering surface tension
and cohesive binding of the liquid phase.
• A typical example is Simethicone (polydimethylsiloxane-
silicon dioxide), which is used at levels of 1-50ppm.
 Of course, a foam is also a very valid dosage form option
for certain situations,
 e.g. for topical administration and in wound dressings.
In addition, granulation using a foam rather than
aqueous granulation fluid is gaining popularity.
 Thickening Agents
• Suspension stabilisers: prevent settling/sedimentation
(particularly if a wetting agent present)
• They usually modify viscosity and are often thixotropic
(where viscosity is dependent on applied shear and
exhibits ‘shear thinning’)
• Easily poured when shaken
• Quickly reforms ‘gel-like’ structure
• They can impact on flocculation at low levels
 Thickening Agents
• Work by entrapment of solid particles, e.g. API, in a
viscous or even
‘gel-like’ structure
• Can be either water-soluble, e.g. methylcellulose or
hydroxyethylcellulose
• Or water-insoluble, e.g. microcrystalline cellulose
 Sweetening Agents
 Natural sweeteners
– Sucrose; soluble in water (vehicle), colourless, stable
(pH 4-8), increases viscosity;
Arguably the best taste/mouthfeel overall but
cariogenic & calorific → avoid in paediatrics?
– Sorbitol (non-cariogenic, non-calorific - appropriate
for paediatric formulations), but lower sweetness
intensity than sucrose (so you need more) & can
cause diarrhoea
 Sweetening Agents
 Artificial sweeteners
• Regulatory review required – often restricted territories
• Much more intense sweeteners compared with sucrose
• As a consequence the levels are much lower (<0.2%)
• Can impart a bitter or metallic after-taste (hence used in
combination with natural sweeteners), e.g.
• Saccharin, and it’s salts
• Aspartame
• Acesulfam –K
• Sucralose – excellent sweetness, non-cariogenic, low calorie,
wide & growing regulatory acceptability but relatively expensive
 Sweetening Agents
• Sweetening agents are employed in liquid formulations
designed for oral administration specifically to increase the
palatability of the therapeutic agent.
• Example:
• Sucrouse, Saccarine, Aspertame, Sorbitol etc.
• Uses of sweetening agent:
• The main sweetening agents employed in oral preparations are
sucrose, liquid glucose, glycerol, sorbitol, saccharin sodium and
aspartame. Aspartame is an artificial sweetening agent. The
use of artificial sweetening agents in formulations is
increasing . The use of sugars in oral formulations for children
and patients with diabetes mellitus is to be avoided.
 Flavouring Agents
• Supplement and complement a sweetening agent
– Ensures patient compliance (especially in paediatric
formulations – a big issue)
– Can be natural, e.g. peppermint, lemon oils,
– Or artificial e.g. butterscotch, ‘tutti-frutti’ flavour
– Instability can be an issue – combinations can be used to
cover intended product shelf-life
• Taste appreciation is not globally consistent…
– Genetic element: one person’s acceptable taste is
another’s unacceptable taste
– Territorial (cultural?) differences in preference; e.g. US
vs. Japan vs. Europe
 Flavouring Agents
- Regulatory acceptability of flavours needs to be checked
- Different sources, different compositions, different
flavour, e.g. there are >30 different “strawberry flavours”!
 Flavoring agents:
• Flavouring agents are added to increase patient
acceptance. The four basic taste sensations are salty,
sweet, bitter and sour. It has been proposed that certain
flavours should be used to mask these specific taste
sensations.
• Example: Clove oil, citric and syrup, glycerin, rose oil,
orange oil, menthol etc..
 Humectant
A humectant attracts and retains the moisture in the nearby air
via absorption, drawing the water vapor into and/or beneath
the organism/object's surface.
Humectants absorb water vapors from atmosphere till a certain
degree of dilution is attained. Aqueous solutions of humectants
can reduce the rate of loss of moisture.
Ideal properties of humectants :
• It must absorb moisture from atmosphere and retain the same
under the normal conditions of atmospheric humidity.
• It should be colorless or not of too intense color.
• It should have good odor and taste.
• It should be nontoxic and nonirritant.
• It should be noncorrosive to packaging materials
• It should not solidify under normal conditions.
• It should not be too costly.
 Humectants
• Hygroscopic excipients used at ~5% in aqueous
suspensions and emulsions for external application.
• Their function is to retard evaporation of aqueous
vehicle of dosage form:
– To prevent drying of the product after application to
the skin
– To prevent drying of product from the container after
first opening
– To prevent cap-locking caused by condensation onto
neck of container-closure of a container after first
opening
• Examples include:
– propylene glycol
– glycerol
– PEG
Overview thoughts for paediatric dosage forms
• Technical Challenges:
– Good taste and mouth feel (oral liquids,
chewable/dispersible/”melt-in-mouth” units, inhaled,
intranasal)
– Inability to swallow solid dosage forms; needing an
alternative option
– Constraints of dosage form size and volume related to
dose required, e.g. drug solubility in small injection
volumes
– Dosing flexibility
– Physical, chemical and, where appropriate, microbial
stability
– Accuracy of dosing – potentially more of a challenge
with lower doses & dose volumes
– Parenterals: needlephobia
• Important routes: oral, topical, inhaled

Others: rectal, ear / eye / nose drops, injectables.

• A wide range of excipients and dosage forms needs to be

considered.
• A key consideration for paediatric dosage forms is to
understand
• the limitations in the type of excipient that can be used
and also the
• amounts & concentrations that can be administered.
 Solvents/Solvent sweeteners
• Need for oral liquid preparations (that children typically
find easier to swallow) often necessitates:
– Taste-masking; which often relies on sweeteners
– Addition of co-solvents to improve drug solubility …if a
solution is wanted (elegance/mouth feel vs. taste)
• Most commonly used solvent sweeteners are
– Propylene glycol
– Glycerine (Glycerol)
• However, note that it was historical adulteration of oral
medicine with the orally toxic diethylene glycol (used in
anti-freeze, brake and transmission fluids) that led to tragic
consequences:
– Impetus for formation of US Food & Drugs Administration
– Genesis of cGMP’s
 Solvents/Preservatives
Propylene Glycol Toxicity
–Propylene glycol is a general solvent and
antimicrobial preservative used in a wide range of
pharmaceutical preparations including oral liquid,
topical and parenteral preparations (The
development of multi-dose oral liquid and
parenteral preparations necessitates the
requirement for preservative(s) to prevent microbial
contamination as serious microbial infections in the
very young can often be fatal).
• However, it’s use in large volumes in children is
discouraged:
• PG has been associated with cardiovascular, hepatic
and CNS adverse events, especially in neonates
(where the biological half-life is prolonged (~17h)
compared with adults (5h).
• IV parenterals containing PG must be administered
slowly.
• PG also has a laxative action at high oral doses
through osmotic pressure effects.
Solvents
• Ethanol Toxicity
–Widely used as a co-solvent to aid solubility
–In US, maximum permitted quantities in OTC
products:
• <0.5% for children under 6-years
• <5% for children 6-12-years
• <10% for children over 12-years
–May cause adverse symptoms of intoxication,
lethargy, stupor, coma, respiratory depression and
cardiovascular collapse.
• Peanut Oil Toxicity
- Peanut oil is used as a food additive and as a
solvent in intra-muscular injections
- It has been suggested that the use of peanut
oil in childhood (infant formula and topical
preparations) can lead to later episodes of
hypersensitivity, and therefore should be
discontinued
 Sweeteners
• Saccharin
–Restricted regulatory acceptability
–Poor aftertaste
–Hypersensitivity reactions; mainly dermatologic
–Paediatrics with allergy to sulphonamides should avoid
saccharin
• Aspartame Toxicity
–Source of phenylalanine – possibly an issue for
phenylketoneurics
–Aspartame has been blamed for hyperactivity in children
but as yet unproven
• Sorbitol
–Can induce diarrhoea
 Preservatives
• Benzyl Alcohol toxicity in neonates
–Widely used as a preservative in cosmetics, foods and
pharmaceuticals (including injectables and oral liquids)
–Toxic syndrome observed in neonates – it was
attributed to the practice of “flushing out” umbilical
catheters with solutions containing benzyl alcohol,
because of trace levels of benzaldehyde that were
present.
–Dilution of nebulisation solutions with BA-preserved
saline led to severe respiratory complications and even
death in neonates. Attributed to accumulation of BA
due to an immature metabolic capability.
 Preservatives
• Sodium Benzoate toxicity
–Widely used as a preservative in cosmetics, foods and
pharmaceuticals (including injectables and oral liquids)
–Injectable combinations of Na Benzoate and Caffeine should not
be used in neonates; found to elicit non-immunological contact
reactions, including urticaria and atopic dermatitis
–Limitation on dosing of NA benzoate to neonates -
≤10mg/kg/day – due to immature metabolic capability
• Thimerosal toxicity
–Formerly widely used as a preservative in cosmetics, in soft
contact lens solutions and pharmaceuticals (primarily vaccines)
–Being phased out from most paediatric vaccines as better
options emerge
–Possible links with toxicity in paediatric vaccines, e.g. linked with
childhood autism but not proven
 Diluents/Fillers
• Lactose toxicity (immature metabolism)

– Lactose occurs widely in dairy products and is used in infant feed formulae.

– In pharmaceutical preparations it is widely used as a diluent in tablets and capsules,

in lyophilised powders, as a sweetener in liquid formulations and as a carrier in dry
powder inhalation products.

– Lactose intolerance occurs when there is a deficiency in the intestinal enzyme

lactase, leading to GIT build-up of lactose. There is then the risk of abdominal
bloating and cramps.

– Lactase is normally present at high levels at birth, declining rapidly in early

childhood (4-8 years) . Hypolactasia (malabsorption of lactose) can thus occur at an
early age and, furthermore, this varies among different ethic groups.

– Significant lactose intolerance can also occur in adults but this is rare.
Acidifying and Alkalizing agents

• Acidifying agent: Agent that have the capacity

to acidify, or confer acidity.
• Alkalizing agents: Agent that have the capacity
to alkalinize, or confer alkalinity.
Surfactants : Surfactants are compounds that lower the surface tension (or
interfacial tension) between two liquids or between a liquid and a solid and
increase the solubility. They are also known as surface active agents.

Properties of surfactants : A surfactant must fulfill two structural requirements:

a) A surfactant must contain a lipophilic region.
b) A surfactant must contain a hydrophilic region.
•
• In a surfactant both hydrophilic and lipophilic region must be balanced
because then both the regions will be concentrated at an interface and
therefore surface tension will be lowered.
Types of surfactants :
There are of four types of surfactants based on the charge of the hydrophilic
region :

1. Anionic surfactant ( here the hydrophilic region is negatively charged i.e. an

anion)
Sodium lauryl sulphate - It is used as an excipient on some
dissolvable aspirins and other fiber therapy caplets.
2. Cationic surfactant (here hydrophilic region is positively charged i.e. a cation)

Cetyl trimethyl ammonium bromide ( cetrimide ) - is an effective antiseptic agent

against bacteria and fungi.

3. Non-ionic surfactants :

• Tween 80 ( polyoxyethylene sorbitol monooleate)- Polysorbate 80 is

an excipient that is used to stabilize aqueous formulations of medications
for parenteral administration

• Span ( sorbitan ester of lauric acid )

4. Amphoteric surfactant :

• Lecithin- it acts as a wetting, stabilizing agent and a choline enrichment carrier,

helps in emulsifications and encapsulation, and is a good dispersing agent.
• N-dodecyl alanine.
Reference Book
• Handbook of Pharmaceutical Excipients, Fifth
Edition.
• Edited by: Raymond C Rowe, Paul J Sheskey
and Siân C Owen.