title: Rapid Method Development in Hydrophilic Interaction Liquid Chromatography for Pharmaceutical Analysis Using a Combination of Quantitative Structure-Retention Relationships and Design of Experiments.
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.
authors.affiliation: Australian Centre for Research on Separation Science (ACROSS), School of Physical Sciences-Chemistry, University of Tasmania , Private Bag 75, Hobart 7001, Australia.
authors.forename: Maryam
authors.initials: M
authors.lastname: Taraji
authors.affiliation: Australian Centre for Research on Separation Science (ACROSS), School of Physical Sciences-Chemistry, University of Tasmania , Private Bag 75, Hobart 7001, Australia.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Haddad
authors.affiliation: Australian Centre for Research on Separation Science (ACROSS), School of Physical Sciences-Chemistry, University of Tasmania , Private Bag 75, Hobart 7001, Australia.
authors.forename: Ruth I J
authors.identifier: 0000-0002-8642-4909
authors.initials: RI
authors.lastname: Amos
authors.affiliation: Australian Centre for Research on Separation Science (ACROSS), School of Physical Sciences-Chemistry, University of Tasmania , Private Bag 75, Hobart 7001, Australia.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Talebi
authors.affiliation: Pfizer Global Research and Development, Sandwich, United Kingdom.
authors.forename: Roman
authors.initials: R
authors.lastname: Szucs
authors.affiliation: LC Resources, McMinnville, Oregon, United States.
authors.forename: John W
authors.initials: JW
authors.lastname: Dolan
authors.affiliation: Thermo Fisher Scientific, Sunnyvale, California, United States.
authors.forename: Chris A
authors.identifier: 0000-0003-2529-3201
authors.initials: CA
authors.lastname: Pohl
mesh_terms: D000465:Algorithms; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D016000:Cluster Analysis; D057927:Hydrophobic and Hydrophilic Interactions; D008956:Models, Chemical; D015394:Molecular Structure; D004364:Pharmaceutical Preparations / Q000032:analysis*; D021281:Quantitative Structure-Activity Relationship; D015203:Reproducibility of Results; D012107:Research Design
chemical_list: D004364:Pharmaceutical Preparations