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Chemical Stability of the Botanical Drug Substance Crofelemer: A Model System for Comparative Characterization of Complex Mixture Drugs.
J Pharm Sci 2017; 106(11):3257-3269JP

Abstract

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.

Authors+Show Affiliations

Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, Kansas 66047.Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, Kansas 66047.Department of Physics and Astronomy, University of Kansas, Lawrence, Kansas 66047.Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, Kansas 66047.Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, Kansas 66047; Macromolecule and Vaccine Stabilization Center, University of Kansas, Lawrence, Kansas 66047.Center for Drug Evaluation and Research, Office of Pharmaceutical Quality, U.S. Food and Drug Administration, Silver Spring, Maryland 20993.Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, Kansas 66047; Macromolecule and Vaccine Stabilization Center, University of Kansas, Lawrence, Kansas 66047.Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, Kansas 66047; Macromolecule and Vaccine Stabilization Center, University of Kansas, Lawrence, Kansas 66047.Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, Kansas 66047.Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, Kansas 66047; Macromolecule and Vaccine Stabilization Center, University of Kansas, Lawrence, Kansas 66047.Center for Computational Biology, University of Kansas, Lawrence, Kansas 66047; Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas 66047; Santa Fe Institute, Santa Fe, New Mexico 87501.Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, Kansas 66047. Electronic address: schoneic@ku.edu.

Pub Type(s)

Comparative Study
Journal Article
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

28688843

Citation

Hewarathna, Asha, et al. "Chemical Stability of the Botanical Drug Substance Crofelemer: a Model System for Comparative Characterization of Complex Mixture Drugs." Journal of Pharmaceutical Sciences, vol. 106, no. 11, 2017, pp. 3257-3269.
Hewarathna A, Mozziconacci O, Nariya MK, et al. Chemical Stability of the Botanical Drug Substance Crofelemer: A Model System for Comparative Characterization of Complex Mixture Drugs. J Pharm Sci. 2017;106(11):3257-3269.
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), pp. 3257-3269. doi:10.1016/j.xphs.2017.06.022.
Hewarathna A, et al. Chemical Stability of the Botanical Drug Substance Crofelemer: a Model System for Comparative Characterization of Complex Mixture Drugs. J Pharm Sci. 2017;106(11):3257-3269. PubMed PMID: 28688843.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Chemical Stability of the Botanical Drug Substance Crofelemer: A Model System for Comparative Characterization of Complex Mixture Drugs. AU - Hewarathna,Asha, AU - Mozziconacci,Olivier, AU - Nariya,Maulik K, AU - Kleindl,Peter A, AU - Xiong,Jian, AU - Fisher,Adam C, AU - Joshi,Sangeeta B, AU - Middaugh,C Russell, AU - Forrest,M Laird, AU - Volkin,David B, AU - Deeds,Eric J, AU - Schöneich,Christian, Y1 - 2017/07/05/ PY - 2017/03/22/received PY - 2017/06/20/revised PY - 2017/06/27/accepted PY - 2017/7/10/pubmed PY - 2018/6/1/medline PY - 2017/7/10/entrez KW - HPLC KW - chemical stability KW - complex mixture KW - crofelemer KW - machine learning KW - mass spectrometry KW - mutual information scores KW - oxidation SP - 3257 EP - 3269 JF - Journal of pharmaceutical sciences JO - J Pharm Sci VL - 106 IS - 11 N2 - 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. SN - 1520-6017 UR - https://www.unboundmedicine.com/medline/citation/28688843/Chemical_Stability_of_the_Botanical_Drug_Substance_Crofelemer:_A_Model_System_for_Comparative_Characterization_of_Complex_Mixture_Drugs L2 - https://linkinghub.elsevier.com/retrieve/pii/S0022-3549(17)30493-8 DB - PRIME DP - Unbound Medicine ER -