Formulation in Pharmacy Practice   2nd Edition

PHENOBARBITONE / PHENOBARBITONE SODIUM
 
 
The solubility of phenobarbitone is approximately 1mg per mL in water and 100mg per mL in alcohol.
Phenobarbitone sodium is very soluble in water (1 in 3) and soluble in alcohol (1 in 25).  Phenobarbitone may be precipitated from solutions of phenobarbitone sodium depending on the pH, concentration and presence of other solvents.1

Phenobarbitone elixir is commercially available in some countries and official formulations exist.  Some of these preparations (e.g. Phenobarbitone Elixir BP and Phenobarbitone Elixir BPC) contain over 30% ethanol which is unacceptably high.  Alcohol free preparations are now recommended especially for neonates and infants.

The following is an alcohol free, official formulation with a discussion of important points and possible alternatives.

Formula 2

Phenobarbitone Sodium Mixture CF
15mg per 5mL
 
Phenobarbitone sodium 300  mg
Glycerol 20  mL
Sorbitol 30  mL
Parabens 0.1  %
Water to   100  mL
 
Expiry:  30 days suggested.
 
Storage:  Room temperature.  Protect from light.
 

 
NOTES and ALTERNATIVES
  1. Sorbitol may be unnacceptable or unavailable.  Omitting this agent is unlikely to compromise short term stability.  If the sorbitol is left out increase the glycerol content from 20% to 40% (ie to 40mL per 100mL)
  2. Different strengths can be prepared if required.
  3. Phenobarbitone sodium solutions are susceptible to precipitation especially if the pH drops
    below 8.5 - 9.  Acidic flavours and syrups should not be added.  If possible check the final pH.
    Caregivers should be advised to check and report any signs of precipitation.
  4. The use of tablets to make phenobarbitone sodium mixture is not recommended as tablet excipients may influence the pH, and it is not possible to observe for precipitation of phenobarbitone due to the insoluble tablet excipients.
  5. If phenobarbitone or phenobarbitone sodium tablets must be used to prepare an oral liquid, use the formula above with the inclusion of 7.5% ethanol.  This should be sufficient maintain phenobarbitone in solution and prevent precipitation.  At normal dose volumes this amount of ethanol is not hazardous and many proprietary products contain this amount.
  6. Dilution of phenobarbitone sodium injection.
    Phenobarbitone sodium injection is usually formulated with ethanol and propylene glycol but dilution with this base may expose an infant to unacceptable amounts of excipients.  Nahata et al3 reported that a commercially available 65mg per mL injection diluted to 10mg per mL with 0.9% Sodium Chloride Injection was stable for four weeks at 4°C.  Over the study period there was no difference in stability between an unadjusted dilution (pH 8.5) and a dilution that was adjusted to pH 10 with sodium hydroxide.  We have observed that dilution of other concentrations and brands can result in precipitation on storage even at a pH of 9, thus the physical stabilty of such dilutions should be closely monitored.

REFERENCES
  1. Tse FL.  Phenobarbital.  In: Connors KA, Amidon GL, Stella VJ.  Chemical Stability of Pharmaceuticals. 2nd Ed. New York: John Wiley, 1986: 655-63.
  2. Australian Pharmaceutical Formulary (APF), 14th Edition.
  3. Nahata MC, Hipple TF, Strausbaugh SD.  Stability of phenobarbital sodium diluted in 0.9% sodium chloride injection.  Am J Hosp Pharm 1986; 43: 384-5.

 
Formulation in Pharmacy Practice
2nd Edition