OBJECTIVES: To evaluate the stability of 12 triazolyl oxazolidinone (TOZ) derivatives in simulated gastric and intestinal fluids as well as in human plasma at 37 ± 1°C. MATERIALS AND METHODS: A stability-indicating high-performance liquid chromatography (HPLC) procedure with a C(8) column (250 × 40 mm, 5 μm particle size) and a mobile phase of acetonitrile/H(2)O (50/50 v/v) at 1.0 ml/min was used. Accelerated stability studies were conducted at 37 ± 1°C in 0.1 M HCl solution as simulated gastric fluid and in phosphate buffer solution (pH about 7.4) as simulated intestinal fluid. The stability of TOZs in human plasma at a simulated biological temperature of 37 ± 1°C was evaluated as well. RESULTS: The stability studies indicated that the examined TOZs were stable in the above media, with the exception of compounds 1a [tert- butyl 4-(4-((R)-5-((1H-1,2,3-triazol-1-yl)methyl)-2-oxooxazolidin-3-yl)-2-fluorophenyl)piperazine-1-carboxylate] and 1b [tert-butyl 4-(2-fluoro-4-((R)-5-((4-methyl-1H-1,2,3-triazol- 1-yl)methyl)-2-oxooxazolidin-3-yl)phenyl) piperazine-1-carboxylate], which underwent degradation in simulated gastric fluid. The degradation kinetics revealed degradation parameters (k(deg), t(1/2), t(90)) of 0.180 h(-1), 3.85 h, and 0.58 h for 1a and of 0.184 h(-1), 3.76 h and 0.57 h for 1b, respectively. Furthermore, the degradation products were identified by mass-spectrometric analysis at mass-to-charge ratios 347.5 and 361.5, respectively, and proton nuclear magnetic resonance analysis. CONCLUSION: With the exception of compounds 1a and 1b, the TOZs are stable in simulated gastric and intestinal fluids as well as in human plasma. Being carbamate derivatives, compounds 1a and 1b underwent fast and complete degradation in simulated gastric fluid. The obtained results should be considered for future studies of formulation of structurally related TOZs in oral dosage forms.
OBJECTIVES: To evaluate the stability of 12 triazolyl oxazolidinone (TOZ) derivatives in simulated gastric and intestinal fluids as well as in human plasma at 37 ± 1°C. MATERIALS AND METHODS: A stability-indicating high-performance liquid chromatography (HPLC) procedure with a C(8) column (250 × 40 mm, 5 μm particle size) and a mobile phase of acetonitrile/H(2)O (50/50 v/v) at 1.0 ml/min was used. Accelerated stability studies were conducted at 37 ± 1°C in 0.1 M HCl solution as simulated gastric fluid and in phosphate buffer solution (pH about 7.4) as simulated intestinal fluid. The stability of TOZs in human plasma at a simulated biological temperature of 37 ± 1°C was evaluated as well. RESULTS: The stability studies indicated that the examined TOZs were stable in the above media, with the exception of compounds 1a [tert- butyl 4-(4-((R)-5-((1H-1,2,3-triazol-1-yl)methyl)-2-oxooxazolidin-3-yl)-2-fluorophenyl)piperazine-1-carboxylate] and 1b [tert-butyl 4-(2-fluoro-4-((R)-5-((4-methyl-1H-1,2,3-triazol- 1-yl)methyl)-2-oxooxazolidin-3-yl)phenyl) piperazine-1-carboxylate], which underwent degradation in simulated gastric fluid. The degradation kinetics revealed degradation parameters (k(deg), t(1/2), t(90)) of 0.180 h(-1), 3.85 h, and 0.58 h for 1a and of 0.184 h(-1), 3.76 h and 0.57 h for 1b, respectively. Furthermore, the degradation products were identified by mass-spectrometric analysis at mass-to-charge ratios 347.5 and 361.5, respectively, and proton nuclear magnetic resonance analysis. CONCLUSION: With the exception of compounds 1a and 1b, the TOZs are stable in simulated gastric and intestinal fluids as well as in human plasma. Being carbamate derivatives, compounds 1a and 1b underwent fast and complete degradation in simulated gastric fluid. The obtained results should be considered for future studies of formulation of structurally related TOZs in oral dosage forms.