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 P-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. (c) 2008 Elsevier B.V. All rights reserved.