Profiling indomethacin impurities using high-performance liquid chromatography and nuclear magnetic resonance

The anti-inflammatory drug indomethacin was investigated regarding new rela ted impurities. Therefore, related substances 2-9 were prepared by independ ent synthesis and physicochemically characterized. To determine indomethaci n and its related substances, a new HPLC-UV method was developed and valida ted. Indomethacin and its impurities were eluted on a C-18 column with a mo bile phase consisting of methanol and an aqueous solution of 0.2% phosphori c acid at a flow rate of 1.5 ml/min and were quantified by UV detection at 320 nm. Overall, the HPLC-UV method was simple and reliable for the detecti on of eight impurities in indomethacin. In addition to the HPLC-UV method, H-1 nuclear magnetic resonance (NMR) was used to investigate indomethacin r egarding impurities. For that purpose, related substances 2-9 were systemat ically added to indomethacin and investigated. The NMR method was found to be very useful for the identification of impurities in bulk substance witho ut prior separation. Both HPLC-UV and NMR were used to analyze 38 batches o f indomethacin available on the European market. The outcome was that 42% o f the batches did not meet the compendial requirements although they met th e specifications of current compendial methods. Some batches contained the previously undescribed impurity 8, while other batches contained by-product s from two distinct synthetic routes. The methods presented herein are impo rtant contributions to the ongoing efforts to reduce impurities and therefo re the risk of adverse side-effects in drugs that are no longer under paten t protection. (C) 2001 Published by Elsevier Science B.V.