Chemical Stability of the Botanical Drug Substance Crofelemer: A Model System for Comparative Characterization of Complex Mixture Drugs

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Issue Date
2017-11-01Author
Hewarathna, Asha
Mozziconacci, Olivier
Nariya, Maulik K.
Kleindl, Peter Alan
Xiong, Jian
Fisher, Adam C.
Joshi, Sangeeta B.
Middaugh, C. Russell
Forrest, M. Laird
Volkin, David B.
Deeds, Eric J.
Schöneich, Christian
Publisher
Elsevier
Type
Article
Article Version
Scholarly/refereed, author accepted manuscript
Rights
© 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
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As the second of a 3-part series of articles in this issue concerning the development of a mathematical model for comparative characterization of complex mixture drugs using crofelemer (CF) as a model compound, this work focuses on the evaluation of the chemical stability profile of CF. CF is a biopolymer containing a mixture of proanthocyanidin oligomers which are primarily composed of gallocatechin with a small contribution from catechin. CF extracted from drug product was subjected to molecular weight–based fractionation and thiolysis. Temperature stress and metal-catalyzed oxidation were selected for accelerated and forced degradation studies. Stressed CF samples were size fractionated, thiolyzed, and analyzed with a combination of negative-ion electrospray ionization mass spectrometry (ESI-MS) and reversed-phase-HPLC with UV absorption and fluorescence detection. We further analyzed the chemical stability data sets for various CF samples generated from reversed-phase-HPLC-UV and ESI-MS using data-mining and machine learning approaches. In particular, calculations based on mutual information of over 800,000 data points in the ESI-MS analytical data set revealed specific CF cleavage and degradation products that were differentially generated under specific storage/degradation conditions, which were not initially identified using traditional analysis of the ESI-MS results.
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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
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Hewarathna, A., Mozziconacci, O., Nariya, M. K., Kleindl, P. A., Xiong, J., Fisher, A. C., … Schöneich, C. (2017). Chemical Stability of the Botanical Drug Substance Crofelemer: A Model System for Comparative Characterization of Complex Mixture Drugs. Journal of pharmaceutical sciences, 106(11), 3257–3269. doi:10.1016/j.xphs.2017.06.022
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