Formulation in Pharmacy Practice   2nd Edition

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Adverse effects due to excipients in drug formulations are generally uncommon but the potential for toxicity is increased at high mg per kg doses especially in neonates and infants.  Dose related toxicity and hypersensitivity reactions are well documented in the literature.1  The subject has been comprehensively reviewed by the American Academy of Pediatrics.13

Methyl and Propyl para-hydroxybenzoates (Parabens)
Parabens are included as an antimicrobial preservative in oral and parenteral preparations.  Parabens are generally safe in neonates because the amount used in formulations is very small.  There is concern that hyperbilirubinaemia can occur in neonates but this has not been demonstrated in vivo.  As a guideline, the intake of parabens should be avoided or minimised in neonates who have jaundice, kernicterus or hyperbilirubinaemia.  There have been several reports of hypersensitivity reactions to oral parabens.  The reactions that have occurred include pruritus, symptoms similar to asthma and delayed urticarial maculopapular rash.1,2

Benzyl Alcohol, Sodium Benzoate and Benzoic Acid
Benzyl alcohol is oxidised in vivo to benzoic acid which is then detoxified by a saturable conjugation pathway in the liver.  The toxicity of benzyl alcohol in neonates is mainly due to its conversion to benzoic acid and subsequent accumulation of the latter.  Consequently, large doses of benzoic acid and sodium benzoate pose a similar risk of toxicity to benzyl alcohol.
A fatal syndrome characterised by gasping and metabolic acidosis was described in very low birth-weight premature infants who received large amounts of parenteral solutions containing benzyl alcohol.3  The compounding factors were the very high mg per kg dose of benzyl alcohol and the immature benzoic acid detoxification pathway.  In infants, the risk of adverse effects due to benzyl alcohol exposure can be estimated on the basis that 100mg/kg/day is the lowest dose reported to have caused death, and that non-fatal toxicity has been reported following a daily intake of 32 - 105mg/kg/day.4  Most oral liquids that contain benzoates (benzyl alcohol, benzoic acid, sodium benzoate) will provide much less than 5mg/kg/day and can be considered relatively safe.  As the dose of benzoate is increased the risk of non-fatal and fatal toxicity will be increased.  For example, the use of preserved doxapram injection at normal therapeutic doses provides a benzyl alcohol exposure in excess of 30mg/kg/day which could be toxic.  As a guideline, a limit of 10mg/kg/day has been arbitrarily suggested.5  If possible, benzoates should be avoided completely in premature, VLBW infants.

Propylene Glycol
Propylene glycol is used as a vehicle in oral and parenteral preparations and has been associated with adverse effects including seizures.6,7  Neonates may be especially susceptible to adverse effects and the total amount administered from all medications should be limited if possible.  Some injections contain large amounts of propylene glycol and this should be considered if the preparation is to be administered orally.

Some proprietary and extemporaneously prepared oral liquids contain up to 30% ethanol.
Administration of such products to infants can constitute a considerable dose of alcohol.  Acute effects include sedation and drowsiness and chronic administration can induce hepatic enzyme systems and alter the clearance of other drugs.  There is also the potential for additive effects with other CNS depressants.
Proprietary preparations containing large amounts of ethanol are still marketed.  The American Academy of Pediatrics8 has arbitrarily established a blood ethanol concentration of 25mg per 100ml as a value that should not to be exceeded following a single dose of ethanol containing medication.
The blood ethanol concentration attained from a dose of ethanol containing medication can be estimated from the following:
  Volume of medication  x  % ethanol v/v  x  0.79
Blood ethanol concentration (mg/100ml)    =   
(adapted from reference 8) 0.6 L/kg  x  Wt (kg)

The specific gravity of absolute ethanol is 0.79.  If the ethanol content of the preparation is expressed as w/v this conversion factor is not required.  The volume of distribution (VD) of ethanol is about 0.6L/kg which approximates total body water.
In premature neonates and infants under six months, the proportion of total body water is greater than in older children and adults.  Although a larger VD will give rise to a lower blood ethanol concentration, little is known about the pharmacokinetics of ethanol in the very young who may be extremely sensitive to its toxic effects.
Example:  Calculate the blood ethanol concentration attained after a single dose of 30mg phenobarbitone (as Phenobarbitone Elixir BP) given to a two-year-old child weighing 10kg.
Phenobarbitone Elixir BP contains 3mg per mL phenobarbitone and 38% v/v ethanol.
    10  x  38  x  0.79  
Blood ethanol concentration (mg/100mL)  =
=    50mg/100mL
    0.6  x  10  
This level would be considered unacceptably high especially if chronic dosing was anticipated.
Several assumptions are made in such estimations but the equation may be used to assess the risk of administering ethanol containing medications.  The effects of accumulation and chronic dosing also require consideration.

Taste is an important issue when making oral formulations for children.  If the medication is not palatable the child will be less likely to take the medication and compliance will be decreased.  Sucrose and syrups should not be used excessively as they can cause dental caries and also provide a significant calorie intake.
Sorbitol is often used as an alternative.  This is a polyol sugar that is poorly absorbed from the small intestine.  It can cause osmotic diarrhoea, gas, bloating and stomach cramps.9  Despite its similarity to glucose and high calorific content, it has little effect on dental plaque pH and is considered non-cariogenic.1

Lactose is used as a filler or diluent in tablets and capsules or to give bulk to powders.  Oral liquids prepared from tablets or capsules containing lactose may cause diarrhoea or gastrointestinal disturbances in lactose or galactose intolerant infants.  The excipient content of most tablet preparations are available from manufacturers or listed in datasheets.

There is a possible link between the oral administration of hypertonic substances and necrotising enterocolitis in the neonate.10,11  Hyperosmolality has also been reported in neonates receiving large amounts of phenobarbitone elixir (1mg/mL) containing glycerol and ethanol.12  Proprietary preparations, enteral feeds and extemporaneously compounded liquids may contribute to these problems and possible cumulative effects should be considered.

There is no doubt that the administration of pharmaceutical excipients can produce adverse effects especially in neonates.  However, the exclusion of co-solvents, stabilisers and preservatives may lead to erratic dosing, chemical degradation and microbial growth.  Some clinicians consider the preservative or ethanol content of some proprietary preparations unacceptably high for use in neonates.  The matter is controversial and discussion of the above factors between pharmacist and paediatrician is essential in deciding on an optimum formulation.
The following points are offered as general guidance:
  • The intake of benzyl alcohol should be avoided or kept to an absolute minimum in neonates, especially VLBW premature babies and those with hyperbilirubinaemia.  Similar cautions probably apply to parabens.  These agents should also be administered with caution to patients with a history of allergy.
  • The intake of ethanol should be minimised but the inclusion of a small amount (e.g. 1 - 5% v/v) is unlikely to be harmful unless relatively large volumes are administered.
  • The concentration of drug in a formulation should be sufficiently high to avoid the administration of large amounts of hypertonic solutions and preservatives.  However, high drug concentrations and small dose volumes pose a potential overdose hazard.
  • Formulations should be kept as simple as possible.
  • The cumulative intake of excipients from all medications and the additive effect of hypertonic formulations should be considered when assessing the potential for adverse effects.
Preservative-Free Preparations
The factors discussed above have created a demand for preservative-free preparations.  Special care must be taken to prevent microbial contamination of such preparations during compounding and subsequent use.  Heavily contaminated excipients (e.g. tragacanth) must be avoided.  The preparation should be stored in a refrigerator and assigned a conservative expiry date even if the drug is chemically stable.  Expiry dates may be extended on satisfactory microbiological evaluation.

  1. Golightly LK, Smolinske SS, Bennett ML, Sutherland EW, Rumack BH.  Pharmaceutical excipients.  Adverse effects associated with 'inactive' ingredients in drug products.  Med Toxicol 1988; 3: 128-165 (Part I) and
    1988; 3: 209-240 (Part II).
  2. Batty KT.  Hypersensitivity to methylhydroxybenzoate:  A case for additive labelling pharmaceuticals.
    Med J Aust 1986; 144: 107.
  3. Gershanik J, Boecler B, Ensley H, McCloskey S, George W.  The gasping syndrome and benzyl alcohol poisoning.  N Engl J Med 1982; 307: 1384 -1388.
  4. Anderson CW, Ng KJ, Andresen B, Cordera L.  Benzyl alcohol poisoning in a premature newborn infant.
    Am J Obstet Gynecol 1984; 148:344-6
  5. Woods D. J.  The safety of antimicrobial preservatives in oral liquids for neonates.  NZ Pharm 1996; 16: 22.
  6. Arulanantham K, Genel M.  Central nervous system toxicity associated with ingestion of propylene glycol.
    J Pediatr 1978; 93:515-6
  7. MacDonald MG, Getson PR, Glasgow AM et al.  Propylene glycol:  Increased incidence of seizures in low birth weight infants.  Pediatrics 1987; 79:622-5
  8. Anon.  American Academy of Pediatrics Committee on Drugs:  Ethanol in liquid preparations intended for children.  Pediatrics 1984; 73: 405-407.
  9. Kumar A, Rawlings RD, Beaman DC.  The mystery ingredients:  sweeteners, dyes, and preservatives in analgesic/antipyretic, antihistamine/decongestant, cough and cold, antidiarrheal, and liquid theophylline preparations.  Pediatrics 1993; 91: 927-933.
  10. Ernst JA, Williams JM, Glick MR, Lemons JA.  Osmolatity of substances used in the intensive care nursery.  Pediatrics 1982; 72: 347-352.
  11. White CC, Harkavy KL.  Hypertonic formula resulting from added oral medications.  Am J Dis Child 1982; 136: 931-933.
  12. Van der Westhuyzen JH, Berger GMB, Beyers N, Moosa A.  Iatrogenic hyperosmolality in a neonate.
    S Afr Med J 1981; 60: 996-998.
  13. Anon.  "Inactive" Ingredients in Pharmaceutical Products:  Update (Subject Review).  Pediatrics 1997; 99(2): 268-278.
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Formulation in Pharmacy Practice
2nd Edition
© 2001 PharmInfoTech
ISBN 0-473-07577-6