Determination of phenobarbital and phenytoin by gas-liquid chromatography with on-column methylation.

Introduction A comprehensive review of gas-chromatographic methods for determining the concentration of circulating antiepileptic drug has been presented (1 ). Because most epileptic patients receive one or more drugs to control their seizures, it is therapeutically desirable to have a method for monitoring the concentrations of each of these drugs in serum. The chemistry of pyrolysis with methylation by gas chromatography has been reviewed extensively (2). The process involves two sequential reactions: (a ) formation of the quaternary N-methyl ammonium salt by deprotonation of the acidic compound with a strongly basic quaternary N-methyl ammonium hydroxide; and (b) thermal decomposition of the salt, upon injection into the chromatograph, to yield a tertiary amine and the methyl derivative. A reagent used for the deprotonation is tetramethyl-ammonium hydroxide in either aqueous or methanolic solution. The chemical structures of the broad spectrum of antiepileptic drugs have in common the potential nitrogen radical for alkylation. The principle of N-methyl derivatization by on-column injection is presented here as a gas-chromatographic method for simultaneous determination of phenobarbital and phenytoin along with potential quantification of other antiepileptic drugs (3-6).