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Abstract

A design-of-experiment (DoE) model was developed, able to describe the retention times of a mixture of pharmaceutical compounds in hydrophilic interaction liquid chromatography (HILIC) under all possible combinations of acetonitrile content, salt concentration, and mobile-phase pH with R2 > 0.95. Further, a quantitative structure–retention relationship (QSRR) model was developed to predict retention times for new analytes, based only on their chemical structures, with a root-mean-square error of prediction (RMSEP) as low as 0.81%. A compound classification based on the concept of similarity was applied prior to QSRR modeling. Finally, we utilized a combined QSRR-DoE approach to propose an optimal design space in a quality-by-design (QbD) workflow to facilitate the HILIC method development. The mathematical QSRR-DoE model was shown to be highly predictive when applied to an independent test set of unseen compounds in unseen conditions with a RMSEP value of 5.83%. The QSRR-DoE computed retention time of pharmaceutical test analytes and subsequently calculated separation selectivity was used to optimize the chromatographic conditions for efficient separation of targets. A Monte Carlo simulation was performed to evaluate the risk of uncertainty in the model’s prediction, and to define the design space where the desired quality criterion was met. Experimental realization of peak selectivity between targets under the selected optimal working conditions confirmed the theoretical predictions. These results demonstrate how discovery of optimal conditions for the separation of new analytes can be accelerated by the use of appropriate theoretical tools.

Item Type:	Article
Authors/Creators:	Taraji, M and Haddad, PR and Amos, RIJ and Talebi, M and Szucs, R and Dolan, JW and Pohl, CA
Keywords:	QSRR, method scoping, HILIC, QbD, DoE
Journal or Publication Title:	Analytical Chemistry
Publisher:	Amer Chemical Soc
ISSN:	0003-2700
DOI / ID Number:	10.1021/acs.analchem.6b04282
Copyright Information:	Copyright 2016 American Chemical Society
Related URLs:	UTAS Profile: Haddad, PR UTAS Profile: Amos, RIJ UTAS Profile: Talebi, M
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