A sensitive and rapid assay for 4-aminophenol in paracetamol drug and tablet formulation, by flow injection analysis with spectrophotometric detection. 
4-Aminophenol (4AP) is the primary degradation product of paracetamol which is limited at a low level (50 ppm or 0.005% w/w) in the drug substance by the European, United States, British and German Pharmacopoeias, employing a manual colourimetric limit test.  The 4AP limit is widened to 1000 ppm or 0.1% w/w for the tablet product monographs, which quote the use of a less sensitive automated HPLC method.  The lower drug substance specification limit is applied to our products, (50 ppm, equivalent to 25 mug 4AP in a tablet containing 500-mg paracetamol) and the pharmacopoeial HPLC assay was not suitable at this low level due to matrix interference.  For routine analysis a rapid, automated assay was required.  This paper presents a highly sensitive, precise and automated method employing the technique of Flow Injection (FI) analysis to quantitatively assay low levels of this degradant.  A solution of the drug substance, or an extract of the tablets, containing 4AP and paracetamol is injected into a solvent carrier stream and merged on-line with alkaline sodium nitroprusside reagent, to form a specific blue derivative which is detected spectrophotometrically at 710 nm.  Standard HPLC equipment is used throughout.  The procedure is fully quantitative and has been optimised for sensitivity and robustness using a multivariate experimental design (multi-level 'Central Composite' response surface) model.  The method has been fully validated and is linear down to 0.01 mug ml(-1).  The approach should be applicable to a range of paracetamol products.