title: Profiling indomethacin impurities using high-performance liquid chromatography and nuclear magnetic resonance.
abstract: The anti-inflammatory drug indomethacin was investigated regarding new related impurities. Therefore, related substances 2-9 were prepared by independent synthesis and physicochemically characterized. To determine indomethacin and its related substances, a new HPLC-UV method was developed and validated. Indomethacin and its impurities were eluted on a C(18) column with a mobile phase consisting of methanol and an aqueous solution of 0.2% phosphoric 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 detection of eight impurities in indomethacin. In addition to the HPLC-UV method, 1H nuclear magnetic resonance (NMR) was used to investigate indomethacin regarding impurities. For that purpose, related substances 2-9 were systematically added to indomethacin and investigated. The NMR method was found to be very useful for the identification of impurities in bulk substance without prior separation. Both HPLC-UV and NMR were used to analyze 38 batches of indomethacin available on the European market. The outcome was that 42% of the batches did not meet the compendial requirements although they met the specifications of current compendial methods. Some batches contained the previously undescribed impurity 8, while other batches contained by-products from two distinct synthetic routes. The methods presented herein are important contributions to the ongoing efforts to reduce impurities and therefore the risk of adverse side-effects in drugs that are no longer under patent protection.
authors.affiliation: Institute of Pharmacy, University of Leipzig, Liebigstrasse 18, D-04103 Leipzig, Germany. sonja_hess@nih.gov
authors.forename: S
authors.initials: S
authors.lastname: Hess
authors.forename: U
authors.initials: U
authors.lastname: Teubert
authors.forename: J
authors.initials: J
authors.lastname: Ortwein
authors.forename: K
authors.initials: K
authors.lastname: Eger
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000032:analysis* / Q000302:isolation & purification*; D002851:Chromatography, High Pressure Liquid / Q000592:standards; D007213:Indomethacin / Q000032:analysis* / Q000138:chemical synthesis / Q000302:isolation & purification*; D019906:Nuclear Magnetic Resonance, Biomolecular / Q000379:methods; D011522:Protons; D015203:Reproducibility of Results; D013056:Spectrophotometry, Ultraviolet / Q000592:standards
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D011522:Protons; D007213:Indomethacin