KINETICS AND MECHANISM OF ACIDIC HYDROLYSIS OF NORDAZEPAM STUDIED BY HIGH-PERFORMANCE LIQUID-CHROMATOGRAPHY AND 4TH-ORDER DERIVATIVE ULTRAVIOLET SPECTROPHOTOMETRY
Ha. Archontaki et al., KINETICS AND MECHANISM OF ACIDIC HYDROLYSIS OF NORDAZEPAM STUDIED BY HIGH-PERFORMANCE LIQUID-CHROMATOGRAPHY AND 4TH-ORDER DERIVATIVE ULTRAVIOLET SPECTROPHOTOMETRY, International journal of pharmaceutics, 167(1-2), 1998, pp. 69-81
A reversed-phase HPLC method was developed to study the acid-catalysed
hydrolysis of nordazepam in hydrochloric acid solutions of 0.01, 0.1
and 1.0 M. One intermediate was observed, which was isolated and ident
ified. The mechanism of hydrolysis appeared to be biphasic, showing a
consecutive reaction with a reversible first step. Initial breakage of
,the azomethine bond, followed by a slow hydrolysis of the amide bond
resulted to creation of the benzophenone product in strongly acidic so
lutions. A fourth-order derivative method for monitoring the parent co
mpound itself was also proposed and evaluated, as well. Relative stand
ard deviation was less than 2% for the HPLC and less than 5% for the d
erivative method. Detection limits for nordazepam, intermediate and fi
nal degradation product were 1.8 x 10(-9) M, 2.1 x 10(-9) M and 2.0 x
10(-9) M, respectively, in the former method and 7.0 x 10(-7) M for no
rdazepam in the latter. Estimation of k(1), k(-1) and k(2) values was
tried and results of HPLC and fourth-order derivative methods were com
pared. (C) 1998 Elsevier Science B.V. All rights reserved.