Polarographic study of flurazepam and its major metabolites

Abstract

The polarographic behaviours of flurazepam, N-1-hydroxyethylflurazepam, flurazepam-N-1-acetic acid, N-1-desalkylflurazepam and N-1-desalkyl-3-hydroxyflurazepam have been systematically studied over the pH range 0–14. Values for pK₁ and pK₃, obtained from a study of E_½versus pH and i_1im.versus pH relationships, corresponding to protonation of the azomethine group and deprotonation of the hydrogen ion attached to the nitrogen atom in position I, respectively, have been determined and are in agreement with those obtained by more accurate spectrophotometric methods. Values of pK₂ corresponding to protonation of the nitrogen atom in the diethylamino side-chain in the first of the above compounds, the carboxylic acid function in the third and the 3-hydroxy function in the last, inaccessible by spectrophotometric methods, have been determined polarographically as 9, 4.5 and 5.5, respectively.

Linear calibration graphs of i_pversus concentration in pH 4 formate buffer were obtained down to 5 × 10^–8M using cathode-ray and differential-pulse polargraphy and were linear over a least three orders of magnitude of concentration for flurazepam and the metabolites listed above. Capsules containing 15 and 30 mg of active constituent were assayed by a method involving cathode-ray polarography and relative standard deviations in the range 0.66–2.66% were obtained.