Gas-chromatographic method for acetaminophen (N-acetyl-p-aminophenol) based on sequential alkylation.

A gas-chromatographic procedure for acetaminophen is described in which the drug is chromatographed as the O-heptyl-N-methyl derivative. This derivative is prepared by a sequential alkylation procedure in which the phenolic hydroxyl group of the parent compound is alkylated off-column with heptyl iodide and the amide group is derivatized on-column by reaction with trimethylanilinium hydroxide. The internal standard, N-propionyl-p-aminophenol, is subjected to the same derivatization procedure. This gas-chromatographic procedure correlates well with conventional colorimetric and spectrophotometric procedures for acetaminophen and is more sensitive. Within-run precision (CV) was 2.0% at a serum concentration of 10.0 mg/liter (n = 10) and between-run precision was 4.0% over a period of eight months. This method is particularly applicable to studies of the pharmacokinetics of acetaminophen.