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Rapid Method Development in Hydrophilic Interaction Liquid Chromatography for Pharmaceutical Analysis Using a Combination of Quantitative Structure–Retention Relationships and Design of Experiments
journal contribution
posted on 2016-12-29, 00:00 authored by Maryam Taraji, Paul R. Haddad, Ruth I. J. Amos, Mohammad Talebi, Roman Szucs, John W. Dolan, Chris A. PohlA 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.