Controlling chloroform content to a safe level in a pharmaceutical oral solution of Chloral hydrate
J T McQuillan, H Hashim, N Woodbridge, K Swaminathan,Abstract
Chloral hydrate is a halogenated hydrocarbon with sedative and hypnotic properties and has been used for its medicinal properties for many years. Its solubility and permeability determine it as a Biopharmaceutical Classification System Class 1 compound, and as such is ideal to be pharmaceutically presented as an aqueous oral liquid presentation. Its primary route of degradation is by hydrolysis to form formic acid and chloroform, and hence licensed pharmaceutical presentations require validated methods to analyse for these degradants. The content of the toxic chloroform degradation product was determined via a head-space gas chromatograph with a flame ionisation detector, and its level was controlled to a safe pharmaceutically acceptable level. This can be achieved by solution pH optimisation in the oral solution, incorporating a buffering system to control the rate of this degradation mechanism.
Where other behavioural and pharmacological therapies have failed for the treatment of short-term severe insomnia, a Chloral hydrate 500mg/5mL Oral Solution presentation with optimised safety profile has been developed as a medication for prescription. Extensive analytical and formulation development work has arrived at a room temperature stable oral solution, with a multi-year expiry date.