title: Assessment of the stability of novel antibacterial triazolyl oxazolidinones using a stability-indicating high-performance liquid chromatography method.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kuwait University, Jabriya, Kuwait. dphillips @ hsc.edu.kw
authors.forename: Oludotun A
authors.initials: OA
authors.lastname: Phillips
authors.forename: Leyla H
authors.initials: LH
authors.lastname: Sharaf
authors.forename: Mohammed E
authors.initials: ME
authors.lastname: Abdel-Hamid
authors.forename: Reny
authors.initials: R
authors.lastname: Varghese
mesh_terms: D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents / Q000097:blood / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects*; D013058:Mass Spectrometry; D023303:Oxazolidinones / Q000097:blood / Q000737:chemistry*; D013270:Stomach / Q000187:drug effects*; D014230:Triazoles / Q000737:chemistry*
chemical_list: D000900:Anti-Bacterial Agents; D000890:Anti-Infective Agents; D023303:Oxazolidinones; D014230:Triazoles