Quantitative Structure-Retention Relationships for Rapid Method Development in Reversed-Phase Liquid Chromatography Yabin Wen M.Sc. Submitted in fulfilment of the requirements for the degree of Doctor of Philosophy School of Physical Sciences University of Tasmania June 2018 i Declaration This thesis contains no material which has been accepted for a degree or diploma by the University or any other institution, except by way of background information and duly acknowledged in the thesis, and to the best of my knowledge and belief no material previously published or written by another person except where due acknowledgement is made in the text of the thesis, nor does the thesis contain any material that infringes copyright. This thesis may be made available for loan and limited copying and communication in accordance with the Copyright Act 1968. The publishers of the papers in this thesis hold the copyright for that content, and access to the material should be sought from the respective journals. The remaining non published content of the thesis may be made available for loan and limited copying and communication in accordance with the Copyright Act 1968. Yabin Wen May 2018 ii Statement of co-authorship The following people and institutions contributed to the publication of work undertaken as part of this thesis: Candidate: Yabin Wen, ACROSS, School of Physical Sciences, UTAS Paul R. Haddad, ACROSS, School of Physical Sciences, UTAS Ruth I.J. Amos, ACROSS, School of Physical Sciences, UTAS Mohammad Talebi, ACROSS, School of Physical Sciences, UTAS Robert Shellie, ACROSS, School of Physical Sciences, UTAS Eva Tyteca, ACROSS, School of Physical Sciences, UTAS Maryam Taraji, ACROSS, School of Physical Sciences, UTAS Soo Hyun Park, ACROSS, School of Physical Sciences, UTAS Roman Szucs, Pfizer Global Research and Development, Sandwich, United Kingdom John W. Dolan, LC Resources, McMinnville, Oregon, United States Chris A. Pohl, Thermo Fisher Scientific, Sunnyvale, California, United States Author details and their roles: Paper 1, “Towards a chromatographic similarity index to establish localised quantitative structure-retention models for retention prediction: use of retention factor ratio”, located in Chapter 3. E. Tyteca (50%), M. Talebi (7%), R.I.J. Amos (7%), Y. Wen (Candidate, 5%), S.H. Park (5%), M. Taraji (5%), R. Szucs (2%), C.A. Pohl (2%), J.W. Dolan (2%), P.R. Haddad (15%). • E. Tyteca was the primary author with P.R. Haddad, M. Talebi, and R.I.J. Amos contributed to the idea, its formulation and development. • P.R. Haddad, M. Talebi and R.I.J. Amos assisted with refinement and presentation. • Y. Wen (Candidate), S.H. Park, and M. Taraji offered retention data and molecular descriptors for the modelling, along with preliminary results for the pilot study, and offered some descriptions in the experimental section of the manuscript. • R. Szucs, C.A. Pohl and J.W. Dolan established the need of study and provided feedback on the work. iii Paper 2, “Retention time prediction based on molecular structure in pharmaceutical method development: A perspective”. M. Talebi (50%), Robert A. Shellie (7%), R.I.J. Amos (7%), Y. Wen (Candidate, 5%), S.H. Park (5%), M. Taraji (5%), R. Szucs (2%), C.A. Pohl (2%), J.W. Dolan (2%), P.R. Haddad (15%). • M. Talebi was the primary author with P.R. Haddad, Robert A. Shellie, and R.I.J. Amos contributed to the idea, its formulation and development. • P.R. Haddad, Robert A. Shellie and R.I.J. Amos assisted with refinement and presentation. • Y. Wen (Candidate), S.H. Park, and M. Taraji offered retention data and molecular descriptors for the modelling, along with preliminary results for the pilot study, and offered some descriptions in the experimental section of the manuscript. • R. Szucs, C.A. Pohl and J.W. Dolan established the need of study and provided feedback on the work. Paper 3, “Retention prediction in reversed phase high performance liquid chromatography using quantitative structure-retention relationships applied to the Hydrophobic Subtraction Model”, located in Chapter 4. Y. Wen (Candidate, 50%), M. Talebi (15%), R.I.J. Amos (15%), R. Szucs (2%), C.A. Pohl (1%), J.W. Dolan (2%), P.R. Haddad (15%). • Y. Wen was the primary author with P.R. Haddad, M. Talebi, and R.I.J. Amos contributed to the idea, its formulation and development. • P.R. Haddad, M. Talebi and R.I.J. Amos assisted with refinement and presentation. • M. Talebi provided general laboratory assistance and GA-PLS algorithm for the modelling. • R. Szucs, C.A. Pohl and J.W. Dolan established the need of study and provided feedback on the work. Paper 4, “Retention index prediction using quantitative structure-retention relationships for improving structure identification in Non-Targeted Metabolomics”, under revision after favourable review, located in Chapter 5. Y. Wen (Candidate, 50%), R.I.J. Amos (15%), M. Talebi (15%), R. Szucs (2%), C.A. Pohl (1%), J.W. Dolan (2%), P.R. Haddad (15%). • Y. Wen was the primary author with P.R. Haddad, M. Talebi, and R.I.J. Amos contributed to the idea, its formulation and development. iv • P.R. Haddad, M. Talebi and R.I.J. Amos assisted with refinement and presentation. • M. Talebi provided general laboratory assistance and GA-PLS algorithm for the modelling. • R. Szucs, C.A. Pohl and J.W. Dolan established the need of study and provided feedback on the work. Signed: Signed: Signed: Paul R. Haddad Ruth I.J. Amos Jason Smith Supervisor Co-Supervisor Head, Discipline of School of Natural School of Natural Chemistry Sciences Sciences School of Natural University of Tasmania University of Tasmania Sciences University of Tasmania v List of publications and presentations Publications: 1. Y. Wen, R.I.J. Amos, M. Talebi, R. Szucs, C.A. Pohl, J.W. Dolan, P.R. Haddad. “Retention index prediction using quantitative structure-retention relationships for improving structure identification in Non-Targeted Metabolomics”, Anal. Chem. 90.15 (2018): 9434-9440. (Chapter 5) 2. Y. Wen, M. Talebi, R.I.J. Amos, R. Szucs, C.A. Pohl, J.W. Dolan, P.R. Haddad. “Retention prediction in reversed phase high performance liquid chromatography using quantitative structure-retention relationships applied to the Hydrophobic Subtraction Model”, J. Chromatogr. A 1541 (2018): 1-11. (Chapter 4) 3. E. Tyteca, M. Talebi, R.I.J. Amos, S.H. Park, M. Taraji, Y. Wen, R. Szucs, C.A. Pohl, J.W. Dolan, P.R. Haddad. “Towards a chromatographic similarity index to establish localised quantitative structure-retention models for retention prediction: use of retention factor ratio”, J. Chromatogr. A 1486 (2017) 50-58. (Chapter 3) 4. M. Talebi, S.H. Park, M. Taraji, Y. Wen, R.I.J. Amos, P.R. Haddad, R.A. Shellie, R. Szucs, C.A. Pohl, J.W. Dolan. “Retention time prediction based on molecular structure in pharmaceutical method development: a perspective”, LCGC North America 34 (8) (2016): 550-558. Presentations: 5. P.R. Haddad, Y. Wen, R.I.J. Amos, M. Talebi, R. Szucs, C.A. Pohl, J.W. Dolan. “Quantitative structure-retention relationships for retention prediction in RPLC and their application to early stage drug development and non-targeted metabolomics”, ISCC 2018, Riva del Garda, Italy. (Oral) 6. Y. Wen, R.I.J. Amos, M. Talebi, R. Szucs, C.A. Pohl, J.W. Dolan, P.R. Haddad. “Retention prediction in reversed-phase high performance liquid chromatography using quantitative structure-retention relationships applied to the Hydrophobic Subtraction Model”, RACI R&D Topics 2017, Hobart, Australia. (Oral) 7. Y. Wen, R.I.J. Amos, M. Talebi, R. Szucs, C.A. Pohl, J.W. Dolan, P.R. Haddad. “Retention prediction in reversed phase HPLC using Quantitative Structure-Retention Relationships applied to the Hydrophobic Subtraction Model”, HPLC 2017, Prague, Czech Republic. (Oral) 8. Y. Wen, P.R. Haddad, R.I.J. Amos, M. Talebi, R. Szucs, C.A. Pohl, J.W. Dolan, R.A. Shellie. “Similarity Searching in Quantitative Structure-Retention Relationship for Retention vi Prediction in Reversed-Phase Liquid Chromatography”, ASASS2 2016, Hobart, Australia. (Oral) 9. P.R. Haddad, S.H. Park, M. Taraji, Y. Wen, E. Tyteca, M. Talebi, R.I.J. Amos, R.A. Shellie, R. Szucs, C.A. Pohl, J.W. Dolan. “Prediction of chromatographic retention times based on chemical structures of analytes”, ASASS2 2016, Hobart, Australia. (Oral) 10. P.R. Haddad, S.H. Park, M. Taraji, Y. Wen, M. Talebi, R.I.J. Amos, R.A. Shellie, R. Szucs, C.A. Pohl, J.W. Dolan. “Role of Structural Similarity in Prediction of Retention in Reversed- Phase, Ion-Exchange and Hydrophilic Interaction Liquid Chromatography Modes Using Quantitative Structure-Retention Relationships”, HPLC 2016, San Francisco, USA. (Oral) 11. P.R. Haddad, S.H. Park, M. Taraji, Y. Wen, E. Tyteca, M. Talebi, R.I.J. Amos, R.A. Shellie, R. Szucs, C.A. Pohl, J.W. Dolan. “Prediction of retention times in reversed-phase, ion- exchange and HILIC modes based on chemical structures”, ISC 2016, Cork, Ireland. (Oral) 12. Y. Wen, M. Talebi, R.I.J. Amos, R.A. Shellie, R. Szucs, C.A. Pohl, J.W. Dolan, P.R. Haddad. “Prediction of retention times in reversed-phase liquid chromatography based on chemical structures of analytes”, RACI R&D Topics 2015, Melbourne, Australia. (Poster) vii Acknowledgements First of all, I would like to offer this thesis to my unborn child, the biggest surprise in my life. I predicted my 33rd year would be a powerful one, now you are the answer. Hope that one day you will be proud of your father. Especially, I would like to sincerely thank my primary supervisor, Prof. Paul Haddad, for his guidance and support throughout my study and my life. Being his last PhD student is an honour, and I will never forget his professionalism, humility, and kindness.