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

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Jesper Larsen, Claus Cornett, Jerzy Witold Jaroszewski, Steen H Hansen

The reactivity of citric acid towards drug substances in the solid state was examined using the beta-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 96h at 50 degrees 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 degrees 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.
Original languageEnglish
JournalJournal of Pharmaceutical and Biomedical Analysis
Volume49
Issue number1
Pages (from-to)11-17
ISSN0731-7085
DOIs
Publication statusPublished - 2009

Bibliographical note

Keywords: Carvedilol; Citric acid; Solid-state reaction; LC-MS; NMR

ID: 9934907