Controlling chloroform content to a safe level in a pharmaceutical oral solution of chloral hydrate

Abstract

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 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 content 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 500 mg/5 ml oral solution presentation with an 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 multiyear expiry date. Key findings: The use of Chloral hydrate in medicinal practice is often associated with high levels of the carcinogen chloroform as a degradation product. The research described herein has shown that the rate of formation of chloroform can be reduced by controlling the impact that the pH has on the stability of the oral solution. The Ph Eur monograph for Chloral hydrate oral solution (unlicensed medicines) does not include a criterion for chloroform quantification, hence Specials manufacturers of this oral solution are potentially risking the safety of patients without appropriate control of chloroform. This research has used validated analytical techniques to support the detection of chloroform, and other possible impurities, thus ensuring a safe product can be provided to the patient.