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Table 3 Excipients known to be harmful and potentially harmful to neonates used in study population, their applications and safety concerns

From: Hospitalised neonates in Estonia commonly receive potentially harmful excipients

Excipient Functional category Applications and typical concentration ranges Safety concern
Known to be harmful to neonates
Parabens (methyl- and propyl parahydroxybenzoate) Antimicrobial Antimicrobial activity against yeasts and molds. Combination of Methyparaben (0.18%) and propylparaben (0.02%) for parenteral formulations. In combinations with propylene glycol (2-5%)/ imidurea Hyperbilirubinemia in neonates. Irritant in injections / ophthalmic drugs. Hypersensitivity reactions. [18, 19]
Saccharin sodium Sweetening 0.02-0.5% w/w* Urticaria with pruritus and photosensitivity reactions. [14]
Sodium benzoate Antimicrobial, tablet / capsule lubricant 0.02-0.5% in oral medicines; 0.5% in parenteral medicines; 2-5% w/w tablet lubricant Contact urticaria. [21] Topical irritant. Increased risk of hyperbilirubinaemia in neonates.
Benzyl alcohol Antimicrobial, solvent Up to 2% v/v* in parenteral/oral preparations, typically 1% v/v. 5% v/v and up used as solubilisers. 10% v/v local anaesthetic properties (parenterals, ophthalmic solutions, oitments) Headache, vertigo, nausea, vomiting, diarrhea, metabolic acidosis, seizures, gasping. Hypersensitivity; fatal toxic syndrome in premature infants. Pain on injection, [8, 1820]
Benzalkonium chloride Antimicrobial, antiseptic, solubilising, wetting Ophthalmic preparations – preservative, 0.01-0.02% w/v*; In combination with other preservatives Ototoxic when applied to ear, skin irritation and hypersensitivity Bronchoconstriction in asthmatics. Eye irritation. [1820]
Propylene glycol Antimicrobial, humectant, plasticizer, solvent, stabilizing, water-miscible cosolvent Humectant – topical – approx.15%. Preservative –solutions / semisolids – 15-30%. Solvent or cosolvent: aerosol solutions 10-30%, oral solutions 10-25%, parenterals 10-60%, topical 5-80% Skin irritation. Central nervous system (CNS) depression. High doses - cardiovascular, hepatic, respiratory adverse events. [1820]
Polysorbate 80 Dispersing, emulsifying, non-ionic surfactant, solubilising, suspending, wetting Emulsifying: alone in oil-in-water emulsions 1-15%; in combination 1-10%. To increase water-holding prop of ointments 1-10%. Solubilising: poorly soluble API*s in lipophilic bases 1-5%; insoluble APIs in lipophilic bases 0.1-3% E-Ferol syndrome - thrombocytopenia, renal dysfunction, hepatomegaly, cholestasis, ascites, hypotension, metabolic acidosis. [18]
Ethanol Solvent In the USA, the max quantity of alcohol included in over the counter (OTC) medicines 0.5% v/v for products for use by children under 6 years of age. Parenteral products containing up to 50% of alcohol (e 95 or 96% v/v) CNS depression - muscle incoordination, visual impairment. Negative synergic effects on CNS when associated with dextromethorfan. Chronic toxicity [8, 18, 20]
Potentially harmful excipients
Sodium metabisulphite Antimicrobial, antioxidant Antioxidant in oral, parenteral, and topical formulations: 0.01–1.0% w/v, intramuscular 27% w/v. Antimicrobial: syrups. Hypersensitivity. Paradoxical bronchospasm, wheezing, dyspnoe and chest tightness in asthmatic children.[1820]
Colloidal anhydrous silica Adsorbent; anticaking; emulsion stabilizer; glidant; suspending; tablet disintegrant; thermal stabilizer; viscosity-increasing Improves flow properties of dry powders (0.1-0.5%) (tabletting); stabilizes emulsions (1.0-5.0%); thixotropic thickening/ suspending (2.0-10.0%); in aerosols to promote particulate suspension, eliminate hard settling, minimize clogging of spray nozzles (0.5-2.0%) A possible sarcoidosis-inducing antigen [22]
Anhydrous sodium hydrogen phosphate (monobasic, dibasic) Buffering; emulsifying; sequestering. Buffering agent; sequestering agent. Concentrations are dependent on the formulation. Gastrointestinal (GI) disturbances including diarrhea, nausea, and vomiting [18]
Sodium bicarbonate Alkalizing; therapeutic. To produce or maintain an alkaline pH in a preparation Exacerbation of chronic heart failure in elderly [18]
Macrogols - polyethylene glycol Ointment base; plasticizer; solvent; suppository base; tablet and capsule lubricant. High molecular weight macrogols can be used as lubricants in tablet formulations; water solubility and bad penetration through skin makes them useful as ointment bases Hypersensitivity reactions, hyperosmolarity, metabolic acidosis, and renal failure in burn patients. [18]
Trometamol Buffering Buffering agent, buffer range from 7.1–9 Hypersensitivity reactions. [23]
Cetostearyl alcohol Emollient; emulsifying; viscosity-increasing. Increasing viscosity; stabilizes emulsions; co-emulsifier; decreasing the amount of surfactant required Hypersensitivity reactions. Contact dermatitis. [18, 19]
Sodium lauryl sulphate Anionic surfactant; detergent; emulsifying; skin penetrant; tablet and capsule lubricant, wetting Tablet lubricant (1.0-2.0%) Irritation to the skin, eyes, mucous membranes, upper respiratory tract, and stomach. [18]
Sorbitan stearate Dispersing; emulsifying; nonionic surfactant; solubilizing; suspending; wetting When used alone produces water-in-oil emulsions / microemulsions. In combination with polysorbate produces water-in-oil or oil-in-water emulsions / creams. Hypersensitive reactions.[18]
Lactic acid Acidulant In injections in the form of lactate as a source of bicarbonate (0.012-1.16%) Neonates have difficulty in metabolizing R-lactic acid, and this isomer and the racemate should therefore not be used in infants aged less than 3 months old. [18]
Sodium cyclamate Sweetening 0.17% w/v as sweeter, in combination with saccharin Photosensitivity. [18]
Disodium edetate Chelating Forms stable water-soluble complexes with alkaline earth and heavy-metal ions; concentrations 0.005-0.1% Local inflammatory reactions. [18]
Gelatin Coating; film-forming; gelling; suspending; tablet binder; viscosity-increasing Tablet binder; microencapsulation Local irritation. Hypersensitivity reactions, including serious anaphylactoid reactions [21]
Povidone Disintegrant; dissolution enhancer; suspending; tablet binder Binder in wet-granulation process; coating; solubilizer for poorly soluble drugs (0.5-5%) Subcutaneous granulomas at the injection site. [21]
Trolamine Alkalizing; emulsifying When mixed in equimolar proportions with a fatty acid an emulsifying agent to produce fine-grained, stable oil-in-water emulsions will be formed (2-4%) Hypersensitivity, skin irritant. [18]
Cresol Antimicrobial preservative; disinfectant. Antimicrobial preservative in parenteral formulations (0.15-0.3%) Skin hypersensitivity reactions. [18]
Maltose Sweetening; tablet diluent Osmotic - ophthalmic drops and parenteral inf. Single report of hyponatremia in a liver transplantation patient. [18]
Sorbic acid Antimicrobial As antimicrobial preservative (0.05-0.2%) Irritant and allergic hypersensitivity skin reactions. [18, 19]
Boric acid Antimicrobial, buffering As antimicrobial preservative in eye drops. Good buffering capacity to control pH. Poisoning - abdominal pain, vomiting, diarrhea, erythematous rash, CNS depression. Convulsions, hyperpyrexia, and renal tubular damage. [18]
Borax Alkalizing; antimicrobial; buffering; disinfectant; emulsifying; stabilizing Antimicrobial preservative in eye preparations Vomiting, diarrhea, erythema, CNS depression, and kidney damage. [18]
Glycine Buffering; bulking; freeze-drying; tablet disintegrant; wetting Cofreeze-dried excipient in injectable formulations Disturbances of fluid and electrolyte balance; cardiovascular and pulmonary disorders. [18]
Calcium chloride dihydrate Antimicrobial, water-absorbing. Dehydrating properties Stomach and heart disturbances. Eye irritant, dermatitis. [18]
Leucine Antiadherent; flavoring; lubricant As antiadherent to improve the deagglomeration Moderately toxic by the s/c route.[18]
Titanium dioxide Coating as opacifier, pigment As a white pigment and opacifier Possibly carcinogenic [24]
Benzethonium chloride Surfactant, antiseptic, wetting and/or solubilizing As an antimicrobial preservative (0.01-0.02% w/v) Probably neurotoxic [25]
Erythrosine Cherry-pink/red synthetic coal tar dye Dye Toxic to human lymphocytes in vitro, binds directly to DNA. [26]
Sodium cetate trihydrate Antimicrobial; buffering; flavoring, stabilizing As a buffering agent and as an antimicrobial preservative Poisonous if injected i/v, an irritant to the skin and eyes. [18]
Ethylendiamine Counter ion Counter ion of theophylline Hypersensitivity reactions [27]
Macrogol cetostearyl ether Emulsifying; penetration enhancer; solubilizing; wetting Solubilizing agent, enhancing effect on the skin permeation Moderately toxic. [18]
Copovidone Film-forming; granulation aid; tablet binder As a film-forming agent (0.5-5%); tablet binder (direct compression and wet granulation) (2.0-5.0%) Moderately toxic by ingestion, gastric disturbances. [18]
Sodium formaldehyde sulfoxylate Antioxidant Antioxidant in parental, rectal solutions Moderately toxic by ingestion, when heated to decomposition it emits toxic fumes. [18]
Castor oil Emollient; oleaginous vehicle; solvent. extended release agent Contact dermatitis. [18]
Acacia Emulsifying; stabilizing; suspending; tablet binder; viscosity-increasing. Viscosity increasing agent (as it is in powder for oral suspensions) Hypersensitivity reactions. [18]
  1. * w/w – weight in weight.
  2. v/v – volume in volume.
  3. w/v – weight in volume.
  4. API – active pharmacutical ingredient.
  5. Source: Ref [18].