Please cite this article in press as: A. Carotti, et al., N-Decyl-S-trityl-(R)-cysteine, a new chiral selector for “green” ligand-exchange chromatography applications, J. Pharm. Biomed. Anal. (2017), http://dx.doi.org/10.1016/j.jpba.2017.02.009 ARTICLE IN PRESS G Model PBA-11072; No. of Pages 10 Journal of Pharmaceutical and Biomedical Analysis xxx (2017) xxx–xxx Contents lists available at ScienceDirect Journal of Pharmaceutical and Biomedical Analysis j o ur na l ho mepage: www.elsevier.com/locate/jpba N-Decyl-S-trityl-(R)-cysteine, a new chiral selector for “green” ligand-exchange chromatography applications Andrea Carotti, Federica Ianni, Emidio Camaioni, Lucia Pucciarini, Maura Marinozzi, Roccaldo Sardella ∗ , Benedetto Natalini Department of Pharmaceutical Sciences, University of Perugia, Via Fabretti 48, 06123 Perugia, Italy a r t i c l e i n f o Article history: Received 8 November 2016 Received in revised form 15 January 2017 Accepted 4 February 2017 Available online xxx Keywords: Chiral ligand-exchange chromatography Green chromatography Sustainable development Food supplement analysis Partition trees a b s t r a c t In search for new enantioselectivity profiles, the N-decyl-S-trityl-(R)-cysteine [C 10 -(R)-STC] was synthe- sized through a one-step procedure and then hydrophobically adsorbed onto an octadecylsilica surface to generate a stable chiral stationary phase for ligand-exchange chromatography (CLEC-CSP) applications. The CLEC analysis was carried out on underivatized amino acids, by using a Cu(II) sulphate (1.0 mM) containing aqueous eluent system. Most of the analysed compounds (34 out of 45) were enantiodis- criminated by the C 10 -(R)-STC-based CSP, with resolution factor (R S ) values up to 8.86. Conformationally rigid and hydrophobic ligands often experienced the largest enantioselectivity effects. A high loadability emerged from the analysis of rac-NorVal (selected as prototype test compound): up to 20 mg/mL were efficiently enantioseparated with the CLEC-CSP. Two in-line hand-made cartridges filled with a strong cation-exchange resin allowed the effective catching of Cu(II) ions after the semi-preparative enantiosep- aration. The quantitative recovery of the rac-NorVal enantiomers was made possible by flowing through the cartridge a 5% (v) ammonia solution. The CLEC phase proved successful in the enantioselective analysis of a commercially available (S)-Leu containing tablet. Furthermore, in order to understand the molec- ular basis for a successful use of the C 10 -(R)-STC-based CLEC system, a descriptive structure-separation relationship study was performed. As a result, all compounds with a MEAN-QPlogS (a hydrophilicity descriptor) value lower than 0.373 can be most likely enantioseparated with the CLEC system under investigation. In the work, the numerous aspects complying with the principles of green chromatography are highlighted and discussed. © 2017 Elsevier B.V. All rights reserved. 1. Introduction The concept of green chemistry was introduced by Anastas in the late 90 s [1]. Since the beginning of the “Green Chemistry Era”, the 12 principles postulated by Anastas became fundamental guidelines for all synthetic chemists fascinated by the paradigm of sustainable development. Almost at the same time, and in response to the outburst of research in the domain of green synthetic chemistry, the urgent need of greening analytical chemistry processes rapidly found broad consensus among analytical chemists. Green analyti- cal chemistry (GAC) essentially focuses on reducing the negative impact of analytical methodologies on the environment while increasing the safety for the operator [2,3]. ∗ Corresponding author. E-mail address: roccaldo.sardella@unipg.it (R. Sardella). Analytical methods based on the use of high-performance liq- uid chromatography (HPLC) systems are the most widely utilized in all sub-fields of chemical research. The huge number of HPLC analyses performed every day around the world both in industrial and academic settings generates an impressive cumulative vol- ume of liquid waste. This unavoidably leads to an urgent need to avail of greener chromatographic methods and techniques. Besides implementing miniaturized analytical devices to shorten the anal- ysis time and reduce the eluent consumption, it is the analyst’s responsibility to replace existing eluent components with greener alternatives with reduced or preferable no negative environmental impact [4–6]. Increased efforts are also directed to find alternative and safer management of wastes from analytical laboratories as well as to reduce sample pretreatment/derivatization steps. Methods exploiting the principle of chiral ligand-exchange chromatography (CLEC) were the first to allow the direct liquid chromatography enantioseparation of the most important classes of underivatized natural and synthetic metal-chelating compounds (amino acids, diamines, amino alcohols, diols, small peptides, etc.) http://dx.doi.org/10.1016/j.jpba.2017.02.009 0731-7085/© 2017 Elsevier B.V. All rights reserved.