Quality-by-design ecofriendly potentiometric sensor for rapid monitoring of hydroxychloroquine purity in the presence of toxic impurities.

Hydroxychloroquine (HCQ) is prescribed to treat malaria and certain autoimmune diseases. Recent studies questioned its efficiency in relieving COVID-19 symptoms and improving clinical outcomes. This work presents a quality-by-design approach to develop, optimize, and validate a potentiometric sensor for the selective analysis of HCQ in the presence of its toxic impurities (key starting materials), namely 4,7-Dichloroquinoline (DCQ) and hydroxynovaldiamine (HND). The study employed a custom experimental design of 16 sensors with different ion exchangers, plasticizers, and ionophores. We observed the Nernstian slopes, correlation coefficients, quantification limit, response time, and selectivity coefficient for DCQ and HND. The computer software constructed a prediction model for each response. The predicted responses strongly correlate to the experimental ones, indicating model fitness. The optimized sensor achieved 93.8% desirability. It proved a slope of 30.57 mV/decade, a correlation coefficient of 0.9931, a quantification limit of 1.07 × 10-6 M, a detection limit of 2.18 × 10-7 M, and a fast response of 6.5 s within the pH range of 2.5-8.5. The sensor was successfully used to determine HCQ purity in its raw material. The sensor represents a potential tool for rapid, sensitive, and selective monitoring of HCQ purity during industrial production from its starting materials.

A sustainable approach for the degradation kinetics study and stability assay of the SARS-CoV-2 oral antiviral drug Molnupiravir.

Molnupiravir (MPV) is the first direct-acting oral antiviral drug that effectively decreases nasopharyngeal infections with SARS-CoV-2 virus. The stability of MPV was tested by subjecting the drug to various stress conditions. The drug is liable to oxidative, acidic, and alkaline degradation and showed significant stability against thermal degradation. Mass spectrometry identified the degradation products and guided suggestion of the degradation patterns. Interestingly, while inspecting the UV-absorption spectra, we observed no absorbance at 270 nm for the products of the three degradation pathways (c.f. intact MPV). Direct spectrophotometry seemed a solution that perfectly fit the purpose of the stability assay method in our case. It avoids sophisticated instrumentation and complex mathematical data manipulation. The method determined MPV accurately (100.32% ± 1.62) and selectively (99.49% ± 1.63) within the linear range of 1.50 × 10-5-4.0 × 10-4 M and down to a detection limit of 0.48 × 10-5 M. The proposed method is simple and does not require any preliminary separation or derivatization steps. The procedure proved its validity as per the ICH recommendations. The specificity was assessed in the presence of up to 90% degradation products. The study evaluated the greenness profile of the proposed analytical procedure using the National Environmental Methods Index (NEMI), the Analytical Eco-Scale, and the Green Analytical Procedure Index (GAPI). The three metrics unanimously agreed that the developed procedure results in a greener profile than the reported method. The method investigated the degradation reactions' kinetics and evaluated the reaction order, rate constant, and half-life time for each degradation process.

Experimentally designed chromatographic method for the simultaneous analysis of dimenhydrinate, cinnarizine and their toxic impurities.

Recently, experimental design has beaten the traditional optimization approach (one variable at a time) by providing better quality for chromatographic separation using minimal effort and resources. Benzophenone (BZP) and [1-(diphenylmethyl)piperazine] (DPP) were reported to be the most toxic impurities for dimenhydrinate (DMH) and cinnarizine (CIN), respectively. Additionally, there is no reported HPLC method for the simultaneous determination of DMH, CIN and their toxic impurities. A custom experimental design was adopted to estimate the optimum conditions that achieved the most acceptable resolution with adequate peak symmetry within the shortest run time. Desirability function was used to define the optimum chromatographic conditions and the optimum separation was achieved using XBridge® HPLC RP-C18 (4.6 × 250 mm, 5 µm), acetonitrile: 0.1% sodium lauryl sulphate (SLS) in water (90 : 10, v/v) as a mobile phase at flow rate 2 mL min-1 and UV detection at 215 nm. Method validation was carried out according to ICH guidelines and linearity was achieved in the ranges of 2-25, 1-25, 1-12.5, and 1-12.5 µg mL-1 for DMH, CIN, BZP and DPP, respectively. By application of the proposed method to the market dosage form, no interference from excipients was observed. Moreover, the greenness of the method was evaluated using the National Environmental Method Index (NEMI), Analytical Eco-Scale and Green Analytical Procedure Index (GAPI) metrics and the results revealed the green environmental impact of the developed method.

Simultaneous estimation of dimenhydrinate, cinnarizine and their toxic impurities benzophenone and diphenylmethylpiperazine; in silico toxicity profiling of impurities.

The British Pharmacopeia (BP) reported that the carcinogenic and hepatotoxic, benzophenone (BZP) is a dimenhydrinate (DMH) impurity. On the other hand, cinnarizine (CIN) is reported to have five impurities (A-E). The toxicity profile of CIN impurities was studied and the in silico data revealed that impurity A [1-(diphenylmethyl)piperazine] (DPP) was the most toxic CIN impurity, and hence it was selected during this work. TLC-densitometric method was developed for separation and simultaneous quantitation of DMH, CIN and their toxic impurities. In the proposed method hexane : ethanol : acetone : glacial acetic acid (7 : 3 : 0.7 : 0.5, by volume) with UV scanning at 225 nm were used. Method validation was carried out according to ICH guidelines and linearity was achieved in the range 0.2-4, 0.5-5, 0.1-2.0, and 0.05-2.2 µg per band for DMH, CIN, BZP and DPP, respectively. On the application of the method to pharmaceutical formulation, no interference from additives was observed. The greenness of the method was evaluated using the analytical eco-scale and the results revealed the low negative environmental impact of the developed method.