Kinetics and Characterization of Degradation Products of Dihydralazine and Hydrochlorothiazide in Binary Mixture by HPLC-UV, LC-DAD and LC–MS Methods

Abstract

Dihydralazine and hydrochlorothiazide were stored at high temperature and humidity, under UV/Vis light and different pH, as individual drugs and the mixture. Then, a sensitive and selective HPLC-UV method was developed for simultaneous determination of dihydralazine and hydrochlorothiazide in presence of their degradation products. Finally, the degradation products were characterized through LC-DAD and LC–MS methods. Dihydralazine was sensitive to high temperature and humidity, UV/Vis light and pH ≥ 7. At the same time, it was resistant to acidic conditions. Hydrochlorothiazide was sensitive to high temperature and humidity, UV/Vis light and changes in pH. Its highest level of degradation was observed in 1 M HCl. Degradation of the drugs was higher when they were stressed in the mixture. In the case of dihydralazine, the percentage degradation was 5–15 times higher. What is more, dihydralazine became sensitive to acidic conditions. Hydrochlorothiazide was shown to be more sensitive to UV/Vis light and pH > 4. Degradation of dihydralazine and hydrochlorothiazide followed first-order kinetics. The quickest degradation of dihydralazine was found to be in 1 M NaOH while of hydrochlorothiazide was in 1 M HCl (individual hydrochlorothiazide) or at pH 7–10 (hydrochlorothiazide in the mixture). A number of new degradation products were detected and some of them were identified by our LC-DAD and LC–MS methods. In the stressed individual samples, (phenylmethyl)hydrazine and 1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide were observed for the first time. Interactions between dihydralazine and hydrochlorothiazide in the mixture were confirmed by additional degradation products, e.g., 2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1,4-trioxide.

Chemical stability and interactions in a new antihypertensive mixture containing indapamide and dihydralazine using FT-IR, HPLC and LC-MS methods

“…So, we concluded for a second time that dihydralazine fragmented by loss of hydrazine and breaking phenazine ring. 16 In our LC-MS studies, products of m/z 121.03 and 161.04 were detected aer degradation in buffer of pH 10 and under UV/VIS light (in a solid state and in methanolic solutions). They were identied as phenylmethylhydrazine and 1hydrazinophthalazine.…”

“…phenylmethylhydrazine and 4dihydrazinylidenophthalazine were described for the rst time in our last paper. 16 When the stressed mixtures of indapamide and dihydralazine were examined, fragment ions of m/z 121.03, 161.04 and 187.04 from dihydralazine (aer degradation in borate buffer of pH 10, 1 M NaOH and under UV/VIS light), as well as of m/z 362.04 from indapamide (aer degradation in all conditions) were detected. In addition, quite new product of degradation of indapamide was detected as a fragment ion of m/z 232.98, as a result of degradation in 1 M HCl, borate buffer of pH 10 and under UV/VIS light (in solid state and in methanolic solution).…”

“…18 As far as chemical stability of dihydralazine was concerned, only one report in this area exists in the literature. 16 In the present study, indapamide and dihydralazine were degraded at high temperature/high humidity, under UV/VIS light and different pH. Then, a FT-IR method was used for preliminary assessment of the stressed solid samples while a new validated HPLC method was applied for quantitative determination of all stressed samples, for percentage levels of degradation as well as for kinetic measurements.…”

“…7,[10][11][12] However, kinetics of degradation of indapamide has not been examined so far. Furthermore, only few HPLC methods have been reported for determination of dihydralazine alone 15 or in the presence of other antihypertensive drugs like hydrochlorothiazide, 16 triamteren 17 and clonidine. 18 As far as chemical stability of dihydralazine was concerned, only one report in this area exists in the literature.…”

Crystal structure and Hirshfeld surface analysis of N-(2-(N-methylsulfamoyl)phenyl)formamide: Degradation product of 2-methyl-2H-1,2,4-benzothiadiazine 1,1-dioxide

“…In the case of HCTZ, studies reveal that hydrolysis led to degradation product identified as 4-amino-6-chlorobenzene-1,3disulfonamide and formaldehyde [13][14][15][16]. Although various by-products are later identified during thiazide hydrolysis [17,18], isolation and full characterization of all degradation products were not reported at all. Qun Xu have proposed a plausible hydrolysis pathway of benzothiadiazine under thermal and humidity conditions showing various intermediates [19].…”