Microchemical Journal 172 (2022) 106918 Available online 25 October 2021 0026-265X/© 2021 Elsevier B.V. All rights reserved. A new grey relational analysis application in analytical chemistry: Natural deep eutectic solvent as a green extractant for HPLC determination of lamotrigine in plasma Noura H. Abou-Taleb a, * , Dina T. El-Sherbiny a, b , Nahed M. El-Enany c , Hussein I. El-Subbagh a a Medicinal Chemistry Department, Faculty of Pharmacy, Mansoura University, 35516 Mansoura, Egypt b Pharmaceutical Chemistry Department, Faculty of Pharmacy, Delta University for Science and Technology, 35712 Gamasa, Egypt c Analytical Chemistry Department, Faculty of Pharmacy, Mansoura University, 35516 Mansoura, Egypt A R T I C L E INFO Keywords: Lamotrigine Natural deep eutectic solvent High performance liquid chromatography Taguchi Grey relational analysis Analytical GREEnness metric approach ABSTRACT Developing new, eco-friendly solvents which would meet technological and economic demands is perhaps the most popular aspects of Green Chemistry. Natural deep eutectic solvents (NADES) fully represent green chem- istry principles. In this sense a new green vortex-assisted NADES-based microextraction (VA-NADES-ME) was established, for the frst time, for the extraction of lamotrigine from human plasma samples using NADES, as a green extractant alternative to hazard organic solvents. Then extract was determined by high performance liquid chromatography with ultraviolet detection (HPLC–UV). The mixture of (choline chloride/ethylene glycol) as NADES was found to be the best candidate for extracting lamotrigine. Grey relational analysis-based Taguchi method was utilized as a chemometric protocol for multiobjective optimization of different HPLC performance parameters. The optimum mobile phase was a mixture of water with 0.3 % triethylamine in 0.02 M H 3 PO 4 (adjusted to pH 5.5) and acetonitrile (70:30 v/v) with an overall pH 6. Finally, the confrmation test was per- formed to validate the predicted optimal results and established an improvement of 32.84 % from the initial design. The mobile phase was eluted in an isocratic mode with a fow rate of 0.8 mL/min and UV detection at 310 nm. The retention times of lamotrigine and tinidazole (internal standard) were 4.7 and 3.4 min, respectively. Proposed method was linear over the concentration range of 0.1–15.0 μg mL 1 . The greenness profle was assessed using Analytical GREEnness metric approach which assured the greenness of the proposed method compared with other reported methods. 1. Introduction Lamotrigine (LMG), is an antiepileptic drug that has been used alone or with other medicines to prevent and control seizures. It may also be used as maintenance treatment in patients with the mental health con- dition bipolar disorder to help delay the occurrence of mood episodes [1]. LMG plasma concentration is 1 to 4 μg mL 1 in patients getting one or more concomitant Anti-Epileptic Drugs [2]. But the most important and prevalent is the toxicity of LMG that signifcantly increases when LMG plasma level is above 15 μg mL 1 [3] in addition to, its large pharmacokinetics variabilities [4–6]. Therefore, plasma concentration monitoring of LMG is very essential for dose adjustment to achieve satisfed effcacy and avoid life-threatening toxicity. The main problem in plasma concentration monitoring is the presence of components such as proteins, DNA, etc. in the complex matrix of the plasma samples. Therefore, before instrumental analysis of the plasma samples, interferences should be eliminated by extraction steps. Liquid–liquid extraction (LLE) and solid-phase extraction (SPE) are the traditional sample preparation methods. However, besides the simplicity and availability of the LLE, this method has some drawbacks, such as using a high volume of toxic organic solvents, low enrichment factors, time-consuming steps, etc. Londero et al extracted LMG from plasma with chloroform-isopropanol after alkalinization with a car- bonate buffer, then back-extracted into 0.05% phosphoric acid and separated by reversed-phase HPLC. Limit of quantitation (LOQ) of 0.2 μg mL 1 was obtained [7]. Saracino et al used SPE followed by HPLC for determination of olanzapine and LMG in plasma samples, using meth- anol as an extraction solvent [8]. Angelis-Stoforidis et al used * Corresponding author. E-mail address: nourahemdan@yahoo.com (N.H. Abou-Taleb). Contents lists available at ScienceDirect Microchemical Journal journal homepage: www.elsevier.com/locate/microc https://doi.org/10.1016/j.microc.2021.106918 Received 5 July 2021; Received in revised form 1 October 2021; Accepted 11 October 2021