Pentabromobenzyl-RP versus triazole-HILIC columns for separation of the polar basic analytes famotidine and famotidone: LC method development combined with in silico tools to follow the potential consequences of famotidine gastric instability

• Published in: Journal of pharmaceutical and biomedical analysis 2020-07, Vol.186, p.113305, Article 113305
• Main Authors: El-Shaheny, Rania, Radwan, Mohamed O., Belal, Fathalla, Yamada, Koji
• Format: Article
• Language: English
• Subjects: Chromatography, Reverse-Phase - methods; Famotidine; Famotidine - analysis; Famotidine - chemistry; Famotidine - pharmacokinetics; Famotidone; Gastric instability; Gastric Juice - metabolism; HILIC; Humans; Hydrogen-Ion Concentration; Hydrophobic and Hydrophilic Interactions; In silico tools; Limit of Detection; Molecular Docking Simulation; RPLC; Silicon Dioxide - chemistry; Solubility; Triazoles - chemistry
• ISSN: 0731-7085; 1873-264X
• DOI: 10.1016/j.jpba.2020.113305

[Display omitted] • Comparison of brominated and triazole columns for separation of polar basic compounds.• The brominated column is superior for separation of famotidine and famotidone.• Kinetic study of famotidine degradation to famotidone in gastric fluid.• A comparative molecular docking study shows weaker hH2R binding of famotidone.• A novel comparative ADMET prediction study of famotidine and famotidone. The competence of hydrophilic interaction (HILIC) and reversed phase liquid chromatography (RPLC) modes, employing two new stationary phases: triazole- and pentabromobenzyl-bonded silica (PBr), respectively, was inspected for separation of two polar basic analytes: famotidine (FAM) and its acidic degradant famotidone (FON). Comparison of the chromatographic efficiency, greenness, and economy aspects showed that the RPLC is superior to the HILIC. Hence, the RPLC method was adopted and validated adhering to the FDA guidelines showing excellent linearity for FAM (1.0−20.0 μg/mL) with a detection limit of 0.14 μg/mL. The method was applied to study the behavior of FAM in simulated gastric juice (SGJ), where it exhibited rapid degradation yielding FON. This degradation pathway is a probable major reason for the poor bioavailability of FAM. The kinetic study of the gastric degradation of FAM in SGJ demonstrated pseudo-first order reaction with a rate constant of 8.1 × 10−3 min-1. Moreover, FAM degradation has been proven to be pH-dependent and catalyzed by the gastric juice components. Hence, in situ buffered dosage form is recommended to overcome or decrease this problem. Molecular docking study shows that FON is missing a crucial stabilizing interaction with the key amino acid Asp98 causing a reduced activity at hH2R receptor relative to FAM. Moreover, ADMET properties prediction revealed some differences in the toxicity, pharmacokinetics, metabolism, and solubility profiles of FAM and FON.