Contents lists available at ScienceDirect Microchemical Journal journal homepage: www.elsevier.com/locate/microc A new strategy for development of eco-friendly RP-HPLC method using Corona Charged Aerosol Detector and its application for simultaneous analysis of risperidone and its related impurities Nevena Maljurić, Biljana Otašević, Jelena Golubović, Jovana Krmar, Mira Zečević, Ana Protić ⁎ Department of Drug Analysis, University of Belgrade – Faculty of Pharmacy, Vojvode Stepe 450, Belgrade, 11152, Serbia ARTICLE INFO Keywords: Green analytical chemistry CAD Ethanol Acetone RP-HPLC GAPI ABSTRACT Green analytical chemistry is primarily directed towards minimization of the amount of waste associated with either the sample preparation or analysis. Among diferent chromatographic methods, liquid chromatography is considered the least green, allowing for various possibilities for greening. Using green solvents such as ethanol or acetone in RP-HPLC, as an alternative to acetonitrile, is recently attracting an attention. Both ethanol and acetone are characterized with low toxicity, with certain drawbacks limiting their regular use in RP-HPLC. Ethanol has low eluotropic strength and causes high backpressures, while acetone shows high UV cut-of, making it unsuitable for UV/Vis detection. To overcome the existing problems, Corona Charged Aerosol Detector was employed for development of RP-HPLC methods for separation of risperidone and its structurally related im- purities with either ethanol or acetone as organic modifer. The methods were optimized by experimental design methodology, while optimal conditions for separation were determined using Derringer's desirability function. Detailed assessment of 3D surface plots of Derringer's desirability function enabled selection of 0.6 mL min −1 fow rate and 20% (v/v) organic modifer content as optimal when using ethanol, while in case of acetone mobile phase fow rate was 0.8 mL min −1 and organic modifer content 17% (v/v). Methods were validated and their eco-friendly character was confrmed through Green Analytical Procedure Index (GAPI). Although both methods are ecologically acceptable, the main drawback is refected in the fact that no recycling or another waste treatment method exist. In the end, acetone was prioritized over ethanol, due to lower health hazard and de- creased amount of generated waste. Corona Charged Aerosol Detector – CAD Green Analytical Procedure Index – GAPI Reversed-Phase High-Performance Liquid Chromatography – RP-HPLC Risperidone – Ris National Fire Protection Association – NFPA International Conference on Harmonization – ICH 1. Introduction Liquid chromatography is considered, generally, less green than for example gas chromatography, as it requires solvents for separation [1, 2]. There are various strategies available for attaching an eco-friendly character to liquid chromatography method. It could be accomplished by using smaller particle size and shorter columns, leading to efcient and fast separations. Apart from stationary phase modifcations, certain mobile phase additives could also lead to development of green liquid chromatography methods. In that respect, supercritical fuids are used as green mobile phases due to benefcial environmental impact and low toxicity [3]. Furthermore, additives such as cyclodextrin could reduce the consumption of organic solvents by inclusion complexation with various drugs and infuence on their retention behaviour [4]. Con- temporary strategy for developing green liquid chromatography methods is utilization of alternative solvents, characterized as „green“. Although the physicochemical characteristics of acetonitrile, as the most commonly used organic solvent in RP-HPLC, are labelling it as golden standard in pharmaceutical analysis, it could be successfully replaced with green alternatives. This research would be directed to- wards investigation of potential of ethanol and acetone as acetonitrile green alternatives, preferred over acetonitrile due to lower toxicity and costs. Further, acetone is characterized with higher eluotropic strength in comparison to methanol, ethanol and acetonitrile, which enables reduced solvent consumption in case of prolonged analyte retention https://doi.org/10.1016/j.microc.2019.104394 Received 23 July 2019; Received in revised form 4 November 2019; Accepted 4 November 2019 ⁎ Corresponding author. E-mail address: anna@pharmacy.bg.ac.rs (A. Protić). Microchemical Journal xxx (xxxx) xxxx 0026-265X/ © 2019 Elsevier B.V. All rights reserved. Please cite this article as: Nevena Maljurić, et al., Microchemical Journal, https://doi.org/10.1016/j.microc.2019.104394