The self-association of the drug acemetacin and its interactions and stabilization with β-cyclodextrin in aqueous solution as inferred from NMR spectroscopy and HPLC studies

Abstract

Strongly concentration dependent, 1H NMR chemical shifts of the non-steroidal anti-inflammatory drug acemetacin sodium salt (sodium {[1-(4-chlorobenzoyl)-5-methoxy-2-methylindol-3-yl]acetoxy}acetate), were observed in aqueous solution. Self-titration and nOe experiments, point to a self-association model where stacking takes place via the indole portion of the drug. In addition, conformational isomerism (atropisomerism) of the anti to syn form was confirmed. Further increase of the concentration eventually led to stable chemical shifts and nearly simultaneous appearance of microcrystals. In the presence of βCD, 1:1 inclusion complexation occurred through the p-chlorobenzoyl part of the drug, whereas with excess βCD the indole part seemed to participate to a minor degree. The anti isomer is suggested to be involved in the inclusion process. In addition, aggregation of acemetacin was also evident, as competing with the conformational and inclusion equilibria. The present case demonstrates that many competitive processes are simultaneously active in a seemingly simple system. The measurements were strongly dependent upon the pH and use of buffered solutions was mandatory. Finally, for the quantitative analysis of acemetacin in the presence of βCD, a special HPLC method was developed. The stability of the drug, studied by the identification of the degradation products and the pseudo-first order rate of hydrolysis, was found to be unaffected by the presence of βCD.