Table 3: Excipients known to be harmful and potentially harmful to neonates used in study population, their applications and safety concerns.
Excipient
Functional category†
Applications and typical concentration
ranges†
Safety concern
Antimicrobial activity against yeasts and
Hyperbilirubinemia in neonates. Irritant
propyl
molds. Combination of Methyparaben
in injections / ophthalmic drugs.
parahydroxybenzoate)
(0.18%) and propylparaben (0.02%) for
Hypersensitivity reactions. [17,18]
Known to be harmful to neonates
Parabens (methyl- and
Antimicrobial
parenteral formulations. In combinations
with propylene glycol (2-5%)/ imidurea
Saccharin sodium
Sweetening
0.02-0.5% w/w*
Urticaria with pruritus and
photosensitivity reactions. [14]
Sodium benzoate
Antimicrobial, tablet /
0.02-0.5% in oral medicines; 0.5% in
Contact urticaria. [20] Topical irritant.
capsule lubricant
parenteral medicines; 2-5% w/w tablet
Increased risk of hyperbilirubinaemia in
lubricant
neonates.
Benzyl alcohol
Antimicrobial, solvent
Up to 2% v/v* in parenteral/oral
Headache, vertigo, nausea, vomiting,
preparations, typically 1% v/v.
diarrhea, metabolic acidosis, seizures,
5% v/v and up used as solubilisers. 10%
gasping. Hypersensitivity; fatal toxic
v/v local anaesthetic properties
syndrome in premature infants. Pain on
(parenterals, ophthalmic solutions,
injection, [8,17-19]
oitments)
Benzalkonium chloride
Antimicrobial, antiseptic,
Ophthalmic preparations – preservative,
Ototoxic when applied to ear, skin
solubilising, wetting
0.01-0.02% w/v*;
irritation and hypersensitivity
In combination with other preservatives
Bronchoconstriction in asthmatics. Eye
irritation. [17-19]
Propylene glycol
Antimicrobial, humectant,
Humectant – topical – approx.15%.
Skin irritation. Central nervous system
plasticizer, solvent,
Preservative –solutions / semisolids – 15-
(CNS) depression. High doses -
stabilizing, water-miscible
30%. Solvent or cosolvent: aerosol
cardiovascular, hepatic, respiratory
cosolvent
solutions 10-30%, oral solutions 10-25%,
adverse events. [17-19]
parenterals 10-60%, topical 5-80%
Polysorbate 80
Dispersing, emulsifying,
Emulsifying: alone in oil-in-water
E-Ferol syndrome - thrombocytopenia,
non-ionic surfactant,
emulsions 1-15%; in combination 1-10%.
renal dysfunction, hepatomegaly,
solubilising, suspending,
To increase water-holding prop of
cholestasis, ascites, hypotension,
wetting
ointments 1-10%. Solubilising: poorly
metabolic acidosis. [17]
soluble API*s in lipophilic bases 1-5%;
insoluble APIs in lipophilic bases 0.1-3%
Ethanol
Solvent
In the USA, the max quantity of alcohol
CNS depression - muscle
included in over the counter (OTC)
incoordination, visual impairment.
medicines 0.5% v/v for products for use by
Negative synergic effects on CNS when
children under 6 years of age. Parenteral
associated with dextromethorfan.
products containing up to 50% of alcohol
Chronic toxicity [8,17,19]
(e 95 or 96% v/v)
Potentially harmful excipients
Sodium metabisulphite
Antimicrobial, antioxidant
Antioxidant in oral, parenteral, and topical
Hypersensitivity. Paradoxical
formulations: 0.01–1.0% w/v,
bronchospasm, wheezing, dyspnoe and
intramuscular 27% w/v. Antimicrobial:
chest tightness in asthmatic children.
syrups.
[17-19]
Colloidal anhydrous
Adsorbent; anticaking;
Improves flow properties of dry powders
A possible sarcoidosis-inducing antigen
silica
emulsion stabilizer;
(0.1-0.5%) (tabletting); stabilizes
[21]
glidant; suspending; tablet
emulsions (1.0-5.0%); thixotropic
disintegrant; thermal
thickening/ suspending (2.0-10.0%); in
stabilizer; viscosity-
aerosols to promote particulate suspension,
increasing
eliminate hard settling, minimize clogging
of spray nozzles (0.5-2.0%)
Anhydrous sodium
Buffering; emulsifying;
Buffering agent; sequestering agent.
Gastrointestinal (GI) disturbances
hydrogen phosphate
sequestering.
Concentrations are dependent on the
including diarrhea, nausea, and vomiting
formulation.
[17]
(monobasic, dibasic)
Sodium bicarbonate
Alkalizing; therapeutic.
To produce or maintain an alkaline pH in a
Exacerbation of chronic heart failure in
preparation
elderly [17]
Macrogols - polyethylene Ointment base; plasticizer;
High molecular weight macrogols can be
Hypersensitivity reactions,
glycol
solvent; suppository base;
used as lubricants in tablet formulations;
hyperosmolarity, metabolic acidosis,
tablet and capsule
water solubility and bad penetration
and renal failure in burn patients. [17]
lubricant.
through skin makes them useful as
ointment bases
Trometamol
Buffering
Buffering agent, buffer range from 7.1–9
Hypersensitivity reactions. [22]
Cetostearyl alcohol
Emollient; emulsifying;
Increasing viscosity; stabilizes emulsions;
Hypersensitivity reactions. Contact
viscosity-increasing.
co-emulsifier; decreasing the amount of
dermatitis. [17,18]
surfactant required
Sodium lauryl sulphate
Anionic surfactant;
Tablet lubricant (1.0-2.0%)
Irritation to the skin, eyes, mucous
detergent; emulsifying;
membranes, upper respiratory tract, and
skin penetrant; tablet and
stomach. [17]
capsule lubricant, wetting
Sorbitan stearate
Dispersing; emulsifying;
When used alone produces water-in-oil
nonionic surfactant;
emulsions / microemulsions. In
solubilizing; suspending;
combination with polysorbate produces
wetting
water-in-oil or oil-in-water emulsions /
Hypersensitive reactions. [17]
creams.
Lactic acid
Acidulant
In injections in the form of lactate as a
Neonates have difficulty in metabolizing
source of bicarbonate (0.012-1.16%)
R-lactic acid, and this isomer and the
racemate should therefore not be used in
infants aged less than 3 months old.
[17]
Sodium cyclamate
Sweetening
0.17% w/v as sweeter, in combination with
Photosensitivity. [17]
saccharin
Disodium edetate
Chelating
Forms stable water-soluble complexes with Local inflammatory reactions. [17]
alkaline earth and heavy-metal ions;
concentrations 0.005-0.1%
Gelatin
Coating; film-forming;
Tablet binder; microencapsulation
Local irritation. Hypersensitivity
gelling; suspending; tablet
reactions, including serious
binder; viscosity-
anaphylactoid reactions [20]
increasing
Povidone
Trolamine
Disintegrant; dissolution
Binder in wet-granulation process; coating; Subcutaneous granulomas at the
enhancer; suspending;
solubilizer for poorly soluble drugs (0.5-
tablet binder
5%)
Alkalizing; emulsifying
When mixed in equimolar proportions with Hypersensitivity, skin irritant. [17]
injection site. [20]
a fatty acid an emulsifying agent to
produce fine-grained, stable oil-in-water
emulsions will be formed (2-4%)
Cresol
Antimicrobial
Antimicrobial preservative in parenteral
Skin hypersensitivity reactions. [17]
Maltose
Sorbic acid
preservative; disinfectant.
formulations (0.15-0.3%)
Sweetening; tablet diluent
Osmotic - ophthalmic drops and parenteral
Single report of hyponatremia in a liver
inf.
transplantation patient. [17]
As antimicrobial preservative (0.05-0.2%)
Irritant and allergic hypersensitivity skin
Antimicrobial
reactions. [17,18]
Boric acid
Antimicrobial, buffering
As antimicrobial preservative in eye drops.
Poisoning - abdominal pain, vomiting,
Good buffering capacity to control pH.
diarrhea, erythematous rash, CNS
depression. Convulsions, hyperpyrexia,
and renal tubular damage. [17]
Borax
Alkalizing; antimicrobial;
Antimicrobial preservative in eye
Vomiting, diarrhea, erythema, CNS
buffering; disinfectant;
preparations
depression, and kidney damage. [17]
Buffering; bulking; freeze-
Cofreeze-dried excipient in injectable
Disturbances of fluid and electrolyte
drying; tablet disintegrant;
formulations
balance; cardiovascular and pulmonary
emulsifying; stabilizing
Glycine
wetting
disorders. [17]
Calcium chloride
Antimicrobial, water-
dihydrate
absorbing.
Leucine
Antiadherent; flavoring;
As antiadherent to improve the
lubricant
deagglomeration
Coating as opacifier,
As a white pigment and opacifier
Possibly carcinogenic [23]
Surfactant, antiseptic,
As an antimicrobial preservative (0.01-
Probably neurotoxic [24]
wetting and/or solubilizing
0.02% w/v)
Cherry-pink/red synthetic
Dye
Titanium dioxide
Dehydrating properties
Stomach and heart disturbances. Eye
irritant, dermatitis. [17]
Moderately toxic by the s/c route. [17]
pigment
Benzethonium chloride
Erythrosine
coal tar dye
Sodium cetate trihydrate
Antimicrobial; buffering;
Toxic to human lymphocytes in vitro,
binds directly to DNA. [25]
As a buffering agent and as an
Poisonous if injected i/v, an irritant to
flavoring, stabilizing
antimicrobial preservative
the skin and eyes. [17]
Ethylendiamine
Counter ion
Counter ion of theophylline
Hypersensitivity reactions [26]
Macrogol cetostearyl
Emulsifying; penetration
Solubilizing agent, enhancing effect on the
Moderately toxic. [17]
ether
enhancer; solubilizing;
skin permeation
wetting
Copovidone
Film-forming; granulation
As a film-forming agent (0.5-5%); tablet
Moderately toxic by ingestion, gastric
aid; tablet binder
binder (direct compression and wet
disturbances. [17]
granulation) (2.0-5.0%)
Sodium formaldehyde
Antioxidant
Antioxidant in parental, rectal solutions
sulfoxylate
Moderately toxic by ingestion, when
heated to decomposition it emits toxic
fumes. [17]
Castor oil
Emollient; oleaginous
extended release agent
Contact dermatitis. [17]
Viscosity increasing agent (as it is in
Hypersensitivity reactions. [17]
vehicle; solvent.
Acacia
Emulsifying; stabilizing;
suspending; tablet binder;
viscosity-increasing.
*
w/w – weight in weight
v/v – volume in volume
w/v – weight in volume
API – active pharmacutical ingredient
† Source:
Ref 17
powder for oral suspensions)