Hyphenating sustainability with chemometrics in chromatographic analysis of COVID combo therapy, nirmatrelvir and Molnupiravir, in presence of their overlapping degradation products; blue-green dual evaluation tools

[Display omitted] •First method analyzing synergistic combination of molnupiravir (MNP) and nirmatrelvir (NTV).•First stability indicating method analyzing two drugs in presence of their degradation products using chemometrics.•Chemometrics enhance linearity parameters, sensitivity, greenness and blueness of our chromatographic method.•The stability results indicate no interaction or change in stability behavior of both drugs when co-administered with each other. Thus, this can be used as an empirical basis to initiate clinical trials of this combination for the treatment of COVID-19 patients. Our manuscript managed to hyphenate the novelty and sustainability in one method. A novel combination of molnupiravir (MNP) and nirmatrelvir (NTV) was found to be a potential symbiotic therapy against SARS-CoV-2. Yet, there is no analytical method published for either determination or stability investigation of this combination simultaneously. So, the proposed HPLC technique focused on determination of MNP and NTV in presence of their degradation products. The sustainability was achieved in our method by using chemometrics tools to quantify NTV in presence of its co-eluted degradation product (NTV-D) without excessive time and solvent usage for separation (run time 5 min.). Moreover, the linearity parameters of both MNP and NTV, including correlation coefficient, LOD and LOQ, have been enhanced significantly after chemometrics treatment through convolution of the resultant derivative curves using trigonometric Fourier function. For example, LOQ of MNP decreased from 3.53 to 0.31 µg/mL and for NTV, LOQ decreased from 4.98 to 2.10 µg/mL after chemometrics treatment. The stability results of the proposed method indicates that no interaction or change in stability behavior of both drugs when co-administered with each other. Thus, this can be used as an empirical basis to initiate clinical trials of this combination for the treatment of COVID-19 patients. Additionally, in order to determine the impact of chemometric methods in minimizing analysis time and reducing solvent, energy, and waste consumption, our chemometric methodology is evaluated in terms of greenness and blueness (dichromic assessment) using AGREE and BAGI, respectively. Besides, the method sustainability using Hexagon was evaluated.