Determination of potential genotoxic NDSRIs (Nitrosamine Drug Substance Related Impurities) in Quetiapine Fumarate – antipsychotic medication: (Q)SAR assessment, UPLC-ESI-MS/MS method development, validation and its analytical greenness evaluation

Abstract

Nitrosamine Drug Substance Related Impurities (NDSRIs) are classified as possible human carcinogens by regulatory authorities. 1,4-Dinitrosopiperazine (DNP), 1-nitrosopiperazine (MNP), 11-(4-Nitrosopiperazin-1-yl)dibenzo[b,f][1,4]thiazepine (NDAQ) and 2-(2-(4-nitrosopiperazin-1-yl)ethoxy)ethan-1-ol (NHEEP) are the prime NDSRIs in Quetiapine Fumarate, an antipsychotic medication. In the current study, SDG3 (Good Health and Well-Being), Targets 3.8 and 3.d. were achieved through calculations involving (Q)-SAR methodologies and CPCA scores. SDG9 (Industry, Innovation, and Infrastructure), Target 9.4 was realized by developing a simple and straightforward UPLC-ESI-MS/MS method for simultaneous determination of four NDSRIs and validated as per ICH (Q2 R2) guidelines. Acquity H-Class UPLC system equipped with Waters Xevo TQ-S Micro MS system was used. Agilent Poroshell 120 PFP column with a dimension of 150 × 4.6 mm, and particle size of 2.7 μm was used. The mobile phase consisting of phases – A and B (0.3 % formic acid in water and methanol respectively) was used in gradient mode with a lower run time of 16 min. The LOQ values, with respect to the sample concentrations, were 42.40 ppb, 42.83 ppb, 41.90 ppb and, 156.45 ppb, for DNP, MNP, NDAQ, and NHEEP respectively. The method's linearity was established from a strong correlation (R² > 0.99). The percent relative standard deviation (%RSD) for six replicates was 1.11 %, 1.09 %, 0.88 %, and 0.37 % for DNP, MNP, NDAQ, and NHEEP, respectively, confirming the method's repeatability. Assessed the method's eco-friendliness by greenness tools like the Green Analytical Procedure Index (GAPI), Analytical GREEnness (AGREE), and Analytical Eco-Scale, and found it to be eco-friendly.