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

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

doi:10.1016/j.jpba.2008.09.039

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

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

23 Citations (Scopus)

Abstract

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 language	English
Journal	Journal of Pharmaceutical and Biomedical Analysis
Volume	49
Issue number	1
Pages (from-to)	11-17
ISSN	0731-7085
DOIs	https://doi.org/10.1016/j.jpba.2008.09.039
Publication status	Published - 2009

Keywords

Former Faculty of Pharmaceutical Sciences

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10.1016/j.jpba.2008.09.039

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Reaction between drug substances and pharmaceutical excipients: formation of citric acid esters and amides of carvedilol in the solid state. / Larsen, Jesper; Cornett, Claus; Jaroszewski, Jerzy Witold et al.
In: Journal of Pharmaceutical and Biomedical Analysis, Vol. 49, No. 1, 2009, p. 11-17.

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

abstract = "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.",

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author = "Jesper Larsen and Claus Cornett and Jaroszewski, {Jerzy Witold} and Hansen, {Steen H}",

note = "Keywords: Carvedilol; Citric acid; Solid-state reaction; LC-MS; NMR",

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T2 - formation of citric acid esters and amides of carvedilol in the solid state

AU - Larsen, Jesper

AU - Cornett, Claus

AU - Jaroszewski, Jerzy Witold

AU - Hansen, Steen H

N1 - Keywords: Carvedilol; Citric acid; Solid-state reaction; LC-MS; NMR

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AB - 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.

KW - Former Faculty of Pharmaceutical Sciences

U2 - 10.1016/j.jpba.2008.09.039

DO - 10.1016/j.jpba.2008.09.039

M3 - Journal article

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JO - Journal of Pharmaceutical and Biomedical Analysis

JF - Journal of Pharmaceutical and Biomedical Analysis

IS - 1

ER -

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

Abstract

Keywords

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