Reaction between drug substances and pharmaceutical excipients: Formation of citric acid esters and amides of carvedilol in the solid state

The reactivity of citric acid towards drug substances in the solid state was examined using the β-blocker carvedilol as a model compound. The reaction mixtures were analysed by LC–MS, the reaction products were isolated by preparative HPLC, and the structures were elucidated by microprobe NMR spectroscopy. Heating a mixture of solid carvedilol and solid citric acid monohydrate for 96 h at 50 °C resulted in the formation of about 3% of a symmetrical ester as well as of a number of other reaction products in smaller amounts. Formation of the symmetrical ester was also observed at room temperature. At 70 °C, the amounts of three isomeric esters formed reached 6–8%. The minor reaction products were citric acid amides, O-acetylcarvedilol, and esters of itaconic acid.