Stability-indicating method development and validation for the concurrent determination of darunavir, cobicistat, emtricitabine and tenofovir alafenamide by UPLC in bulk and tablet dosage forms

Abstract

Background Tablet dosage forms containing combination of darunavir a protease inhibitor, cobicistat a cytochrome P450 3A inhibitor, emtricitabine and tenofovir alafenamide which were nucleoside reverse transcriptase inhibitors were approved by USFDA on 1st July 2018 to suppress the viral load in HIV patients. It can be used as a complete regimen for the treatment of HIV-1 infection in adults and paediatric patients weighing at least 40 kg. An UPLC method was developed, and separation was done on SB C8 column of dimensions 50 × 2.1 × 1.8 μ with mobile phase 0.01 N potassium dihydrogen ortho phosphate (pH-4.8) and acetonitrile in 60:40 ratio, at a flow rate of 0.3 mL/min and an injection volume of 2 μL. The column temperature was maintained at 30 °C, and detection wavelength was 267 nm. The method was validated according to ICH guidelines. Results The retention times were 1.031, 1.341, 1.630 and 2.153 min, and they were linear in the concentration range of 1.25–7.5 μg/mL, 18.75–112.5 μg/mL, 25–150 μg/mL and 100–600 μg/mL for tenofovir alafenamide, cobicistat, emtricitabine and darunavir, respectively. The intraday and interday precisions were found to be within acceptable limits. LOD was found to be 0.06 μg/mL, 0.51 μg/mL, 1.31 μg/mL and 3.01 μg/mL, and LOQ was 0.19 μg/mL, 1.54 μg/mL, 3.96 μg/mL and 9.13 μg/mL for tenofovir alafenamide, cobicistat, emtricitabine and darunavir. The correlation coefficients were found to be more than 0.999, and recovery was more than 99.52% indicating the method was accurate. Forced degradation studies reveal that the drugs are unstable under acidic conditions. The method was simple, accurate, precise, stable and can be analysed in less runtime of 4 min. Conclusions The flexibility, accuracy and precision of the developed method ensure its applicability in routine analysis of tablet dosage forms. Graphical Abstract

Fifty-Nine-Year-Old Woman With Concurrent Administration of Cobicistat and Dexamethasone Potentially Leading to Mania

“…1,3 Cobicistat has been incorporated into multidrug regimens for HIV medications, whereas ritonavir has been used in short-term antiretroviral dosages. 2,4 A consequence of ritonavir and cobicistat usage is potential short or long adverse events with other drugs metabolized by the CYP3A enzyme. For example, because of the COVID-19 pandemic, the Food and Drug Administration granted an emergency use authorization of Paxlovid, Pfizer's combination tablet composed of ritonavir 100 mg and nirmalrelvir 250 mg (N + R).…”

“…Cobicistat, a structural analog of ritonavir, prioritizes ritonavir's efficacy, safety, and tolerability profiles while minimizing HIV protease inhibition and anti-HIV activity in general 1,3 . Cobicistat has been incorporated into multidrug regimens for HIV medications, whereas ritonavir has been used in short-term antiretroviral dosages 2,4 …”