{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T03:27:14Z","timestamp":1788838034353,"version":"build-2803163510"},"reference-count":47,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2019,2,25]],"date-time":"2019-02-25T00:00:00Z","timestamp":1551052800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004488","name":"Hrvatska Zaklada za Znanost","doi-asserted-by":"publisher","award":["IP-2016-06-1142"],"award-info":[{"award-number":["IP-2016-06-1142"]}],"id":[{"id":"10.13039\/501100004488","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>The importance of chirality in drug development is unquestionable, with chiral liquid chromatography (LC) being the most adequate technique for its analysis. Among the various types of chiral stationary phases (CSPs) for LC, brush-type CSPs provide the base for interaction analysis of CSPs and enantiomers, which provide valuable results that can be applied to interaction studies of other CSP types. In order to analyze the influence of aromatic interactions in chiral recognition, we designed a set of ten new brush-type CSPs based on (S)-N-(1-aryl-propyl)-3,5-dinitrobenzamides which differ in the aromatic unit directly linked to the chiral center. Thirty diverse racemates, including several nonsteroidal anti-inflammatory drugs and 3-hydroxybenzodiazepine drugs, were used to evaluate the prepared CSPs. Chromatographic analysis showed that the three new CSPs separate enantiomers of a wide range of compounds and their chromatographic behavior is comparable to the most versatile brush-type CSP\u2014Whelk-O1. The critical role of the nonbonding interactions in positioning of the analyte (naproxen) in the cleft of CSP-6, as well as the analysis of interactions that make enantioseparation possible, were elucidated using computational methods. Furthermore, the influence of acetic acid as a mobile phase additive, on this enantiorecognition process was corroborated by calculations.<\/jats:p>","DOI":"10.3390\/molecules24040823","type":"journal-article","created":{"date-parts":[[2019,2,25]],"date-time":"2019-02-25T10:56:53Z","timestamp":1551092213000},"page":"823","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["New Brush-Type Chiral Stationary Phases for Enantioseparation of Pharmaceutical Drugs"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3736-912X","authenticated-orcid":false,"given":"Anamarija","family":"Kne\u017eevi\u0107","sequence":"first","affiliation":[{"name":"Division of Organic Chemistry and Biochemistry, Ru\u0111er Bo\u0161kovi\u0107 Institute, Bijeni\u010dka cesta 54, Zagreb 10000, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5744-6677","authenticated-orcid":false,"given":"Jurica","family":"Novak","sequence":"additional","affiliation":[{"name":"Division of Physical Chemistry, Ru\u0111er Bo\u0161kovi\u0107 Institute, Bijeni\u010dka cesta 54, Zagreb 10000, Croatia"},{"name":"South Ural State University, 20-A, Tchaikovsky Str., Chelyabinsk 454080, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vladimir","family":"Vinkovi\u0107","sequence":"additional","affiliation":[{"name":"Division of Organic Chemistry and Biochemistry, Ru\u0111er Bo\u0161kovi\u0107 Institute, Bijeni\u010dka cesta 54, Zagreb 10000, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,2,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"(1992). FDA\u2019S policy statement for the development of new stereoisomeric drugs. Chirality, 4, 338\u2013340.","DOI":"10.1002\/chir.530040513"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/j.jpba.2017.07.008","article-title":"The market of chiral drugs: Chiral switches versus de novo enantiomerically pure compounds","volume":"147","author":"Calcaterra","year":"2018","journal-title":"J. Pharm. Biomed. Anal."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.chroma.2004.01.065","article-title":"Chiral liquid chromatography contribution to the determination of the absolute configuration of enantiomers","volume":"1037","author":"Roussel","year":"2004","journal-title":"J. Chromatogr. A"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1218","DOI":"10.1002\/anie.201302823","article-title":"Processes to Separate Enantiomers","volume":"53","author":"Lorenz","year":"2014","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.chroma.2016.05.061","article-title":"Chiral recognition in separation science\u2014An update","volume":"1467","author":"Scriba","year":"2016","journal-title":"J. Chromatogr. A"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"8821","DOI":"10.1021\/acs.analchem.6b02260","article-title":"Salient Sub-Second Separations","volume":"88","author":"Wahab","year":"2016","journal-title":"Anal. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.chroma.2016.09.001","article-title":"Pirkle-type chiral stationary phase on core\u2013shell and fully porous particles: Are superficially porous particles always the better choice toward ultrafast high-performance enantioseparations?","volume":"1466","author":"Ismail","year":"2016","journal-title":"J. Chromatogr. A"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.chroma.2017.04.002","article-title":"Overcoming \u201cspeed limits\u201d in high throughput chromatographic analysis","volume":"1499","author":"Zawatzky","year":"2017","journal-title":"J. Chromatogr. A"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1021\/acscentsci.7b00250","article-title":"Are We Approaching a Speed Limit for the Chromatographic Separation of Enantiomers?","volume":"3","author":"Welch","year":"2017","journal-title":"ACS Cent. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1039\/C6CC08512A","article-title":"Ultrafast chiral separations for high throughput enantiopurity analysis","volume":"53","author":"Barhate","year":"2017","journal-title":"Chem. Commun."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Ismail, O., Felletti, S., Luca, C., Pasti, L., Marchetti, N., Costa, V., Gasparrini, F., Cavazzini, A., and Catani, M. (2018). The Way to Ultrafast, High-Throughput Enantioseparations of Bioactive Compounds in Liquid and Supercritical Fluid Chromatography. Molecules, 23.","DOI":"10.3390\/molecules23102709"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.chroma.2018.08.027","article-title":"On our way to sub-second separations of enantiomers in high-performance liquid chromatography","volume":"1572","author":"Khundadze","year":"2018","journal-title":"J. Chromatogr. A"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"814","DOI":"10.1016\/j.chroma.2009.10.022","article-title":"Chiral recognition by enantioselective liquid chromatography: Mechanisms and modern chiral stationary phases","volume":"1217","year":"2010","journal-title":"J. Chromatogr. A"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1080\/15422110802589916","article-title":"Polysaccharides Chiral Stationary Phases in Liquid Chromatography","volume":"38","author":"Ali","year":"2009","journal-title":"Sep. Purif. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1007\/s10337-013-2469-8","article-title":"Small Molecules as Chromatographic Tools for HPLC Enantiomeric Resolution: Pirkle-Type Chiral Stationary Phases Evolution","volume":"76","author":"Fernandes","year":"2013","journal-title":"Chromatographia"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1080\/15422119.2017.1326939","article-title":"Chiral Stationary Phases Based on Small Molecules: An Update of the Last 17 Years","volume":"47","author":"Fernandes","year":"2018","journal-title":"Sep. Purif. Rev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1002\/chir.20396","article-title":"Role of the weak interactions in enantiorecognition of racemic dihydropyrimidinones by novel brush-type chiral stationary phases","volume":"19","author":"Forjan","year":"2007","journal-title":"Chirality"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1081\/JLC-120017153","article-title":"Enantiomer Separation and Molecular Recognition with New Chiral Stationary Phases on 4-Chloro-3,5-dinitrobenzoic Acid Amides of \u03b1,\u03b2-Aminoalcohols and \u03b1-Arylethylamines","volume":"26","author":"Ranogajec","year":"2003","journal-title":"J. Liq. Chromatogr. Relat. Technol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1002\/(SICI)1520-636X(2000)12:2<63::AID-CHIR2>3.0.CO;2-W","article-title":"Preparation and evaluation of chiral stationary phases based on N,N-2,4-(or 4,6)-disubstituted 4,5-(or 2,5)-dichloro-1,3-dicyanobenzene","volume":"12","author":"Kontrec","year":"2000","journal-title":"Chirality"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3982","DOI":"10.1002\/ejoc.201800346","article-title":"Determination of the Absolute Configuration of (S)-N-(1-Aryl-allyl)-3,5-dinitrobenzamides and Their Elution Order on Brush-Type Chiral Stationary Phases","volume":"2018","author":"Novak","year":"2018","journal-title":"Eur. J. Org. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/0021-9673(94)00753-V","article-title":"Influence of the method of preparation of chiral stationary phases on enantiomer separations in high-performance liquid chromatography","volume":"694","author":"Ihara","year":"1995","journal-title":"J. Chromatogr. A"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1007\/BF02274559","article-title":"The influence of end-capping on the enantioselectivity of a chiral phase","volume":"31","author":"Pirkle","year":"1991","journal-title":"Chromatographia"},{"key":"ref_23","unstructured":"Snyder, L.R., Kirkland, J.J., and Glajch, J.L. (2012). Practical HPLC Method Development, John Wiley & Sons."},{"key":"ref_24","unstructured":"(1970, January 01). Chiral Handbook for HPLC & SFC Separations. Available online: http:\/\/www.registech.com\/literature-library\/technical-resources\/chiral-handbook-for-hplc-sfc-separations."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"8177","DOI":"10.1021\/acs.analchem.7b00931","article-title":"Fundamental and Practical Insights on the Packing of Modern High-Efficiency Analytical and Capillary Columns","volume":"89","author":"Wahab","year":"2017","journal-title":"Anal. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/j.chroma.2007.11.118","article-title":"Particle packed columns and monolithic columns in high-performance liquid chromatography-comparison and critical appraisal","volume":"1184","author":"Unger","year":"2008","journal-title":"J. Chromatogr. A"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3854","DOI":"10.1021\/jo00040a026","article-title":"Design, synthesis, and evaluation of an improved enantioselective naproxen selector","volume":"57","author":"Pirkle","year":"1992","journal-title":"J. Org. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1947","DOI":"10.1080\/10826079208020869","article-title":"An Improved Chiral Stationary Phase for the Chromatographic Separation of Underivatized Naproxen Enantiomers","volume":"15","author":"Pirkle","year":"1992","journal-title":"J. Liq. Chromatogr."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1016\/j.tetasy.2011.06.004","article-title":"An efficient enzymatic approach to (S)-1-aryl-allylamines","volume":"22","author":"Landek","year":"2011","journal-title":"Tetrahedron Asymmetry"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/0021-9673(94)00477-3","article-title":"Chromatographic and 1H NMR support for a proposed recognition model","volume":"683","author":"Pirkle","year":"1994","journal-title":"J. Chromtogr. A"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5968","DOI":"10.1016\/j.chroma.2009.06.041","article-title":"Rational optimization of the Whelk-O1 chiral stationary phase using molecular dynamics simulations","volume":"1216","author":"Zhao","year":"2009","journal-title":"J. Chromatogr. A"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1002\/chir.20009","article-title":"Theoretical reassessment of Whelk-O1 as an enantioselective receptor for 1-(4-halogeno-phenyl)-1-ethylamine derivatives","volume":"16","author":"Hayes","year":"2004","journal-title":"Chirality"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1016\/S0957-4166(00)86225-4","article-title":"Use of Simultaneous Face to Face and Face to Edge \u03c0-\u03c0 Interactions to Facilitate Chiral Recognition","volume":"5","author":"Pirkle","year":"1994","journal-title":"Tetrahedron Asymmetry"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2191","DOI":"10.1039\/c2sc20045g","article-title":"Rethinking the term \u201cpi-stacking\u201d","volume":"3","author":"Martinez","year":"2012","journal-title":"Chem. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2426","DOI":"10.1021\/ac702126y","article-title":"Molecular Dynamics Study of Chiral Recognition for the Whelk-O1 Chiral Stationary Phase","volume":"80","author":"Zhao","year":"2008","journal-title":"Anal. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/S0021-9673(01)01060-3","article-title":"Effect of mobile phase acidic additives on enantioselectivity for phenylalanine analogs","volume":"927","author":"Ye","year":"2001","journal-title":"J. Chromatogr. A"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1002\/chir.20287","article-title":"The effect of acidic and basic additives on the enantioseparation of basic drugs using polysaccharide-based chiral stationary phases","volume":"18","author":"Ye","year":"2006","journal-title":"Chirality"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2529","DOI":"10.1002\/jssc.201200443","article-title":"HPLC separation of dihydropyridine derivatives enantiomers with emphasis on elution order using polysaccharide-based chiral columns: Liquid Chromatography","volume":"35","author":"Jibuti","year":"2012","journal-title":"J. Sep. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.chroma.2013.08.029","article-title":"On the effect of basic and acidic additives on the separation of the enantiomers of some basic drugs with polysaccharide-based chiral selectors and polar organic mobile phases","volume":"1317","author":"Mosiashvili","year":"2013","journal-title":"J. Chromatogr. A"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1002\/chir.22417","article-title":"Effect of Basic and Acidic Additives on the Separation of Some Basic Drug Enantiomers on Polysaccharide-Based Chiral Columns with Acetonitrile as Mobile Phase: SEPARATION OF SOME BASIC DRUG ENANTIOMERS","volume":"27","author":"Gogaladze","year":"2015","journal-title":"Chirality"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"6768","DOI":"10.1021\/j100334a054","article-title":"Self-association of acetic acid in some organic solvents","volume":"92","author":"Fujii","year":"1988","journal-title":"J. Phys. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3086","DOI":"10.1021\/jp027637k","article-title":"Acetic Acid Dimer in the Gas Phase, Nonpolar Solvent, Microhydrated Environment, and Dilute and Concentrated Acetic Acid: Ab Initio Quantum Chemical and Molecular Dynamics Simulations","volume":"107","author":"Vacek","year":"2003","journal-title":"J. Phys. Chem. A"},{"key":"ref_43","unstructured":"Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Scalmani, G., Barone, V., Petersson, G.A., and Nakatsuji, H. (2016). Gaussian 16, Gaussian, Inc.. Revision B.01."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1007\/s00214-007-0310-x","article-title":"The M06 suite of density functionals for main group thermochemistry, thermochemical kinetics, noncovalent interactions, excited states, and transition elements: Two new functionals and systematic testing of four M06-class functionals and 12 other functionals","volume":"120","author":"Zhao","year":"2008","journal-title":"Theor. Chem. Acc."},{"key":"ref_45","unstructured":"Case, D.A., Betz, R.M., Cerutti, D.S., Cheatham, T.E., III, T.A., Darden, R.E., Duke, T.J., Giese, H., Gohlke, A.W., and Goetz, N. (2016). AMBER, University of California."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1039\/P29930000799","article-title":"COSMO: A new approach to dielectric screening in solvents with explicit expressions for the screening energy and its gradient","volume":"5","author":"Klamt","year":"1993","journal-title":"J. Chem. Soc. Perkin Trans. 2"},{"key":"ref_47","unstructured":"(2015). TURBOMOLE 7.0.1, University of Karlsruhe and Forschungszentrum."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/24\/4\/823\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:34:37Z","timestamp":1760186077000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/24\/4\/823"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,2,25]]},"references-count":47,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2019,2]]}},"alternative-id":["molecules24040823"],"URL":"https:\/\/doi.org\/10.3390\/molecules24040823","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,2,25]]}}}