Utility and greenness appraisal of nuclear magnetic resonance for sustainable simultaneous determination of three 1,4-benzodiazepines and their main impurity 2-amino-5-chlorobenzophenone

Abstract

A robust, stability-indicating, and eco-friendly proton nuclear magnetic resonance (1H-qNMR) method was developed for the concurrent determination of three 1,4-benzodiazepines (BDZs), namely diazepam (DZP), alprazolam (ALP), and chlordiazepoxide (CDP) and their common impurity, synthesis precursor, and degradation product; 2-amino-5-chlorobenzophenone (ACB). In the present method, a novel approach was developed for composing a green and cost-efficient solvent system as an alternative to the common NMR organic solvents utilizing 0.3 M sodium dodecyl sulfate prepared in deuterated water. The conducted method is characterized by simplicity with no need for sample pretreatment or labeling. Phloroglucinol was used as an internal standard. The chosen signals for the determinations of ALP, CDP, DZP and ACB were at 2.35 ppm (singlet), 2.84 ppm (singlet), 3.11 ppm (singlet), and 6.90 ppm (doublet of doublet), respectively. The proposed method possessed linearity over the concentration range of 0.25–15.0 mg ml−1 for DZP, ALP, CDP and of 0.5–25.0 mg ml−1 for ACB with LOD values of 0.06, 0.03, 0.07 and 0.16 mg ml−1 respectively, and LOQ values of 0.18, 0.09, 0.21 and 0.49 mg ml−1, respectively. Accuracy of the method was evidenced by excellent recovery% (99.57–99.90%) and small standard deviation (≥ 1.10) for the three analyzed drugs. Intra- and inter-day precision were determined with coefficient of variation ranging from 0.12 to 1.14 and from 0.72 to 1.67, respectively. For the studied compounds, appraisal of the method greenness was achieved via four approaches: Analytical Eco-Scale, Green Analytical Procedure Index (GAPI), Analytical greenness metric (AGREE), and RGB Additive Color Model. The results proved that the proposed method has the privilege of being a green analytical method.