PubMed · 13536400
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1958-04-26. CHLOROTHIAZIDE.. https://pubmed.ncbi.nlm.nih.gov/13536400/
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First derivative and dual-wavelength spectrophotometric methods were used in the quantum yield determination of the photochemical decomposition reactions of three thiazide diuretics (chlorothiazide, hydrochlorothiazide and trichloromethiazide) in ethanolic solution. The radiation absorbed by the compounds was measured using iron(III) oxalate actinometry based on absorption spectrophotometry. An apparatus is described in which the drugs were irradiated in quartz cuvettes cooled by water in a stand built on a magnetic stirrer. The wavelength region available to the reaction cuvette was restricted to 313 nm with chemical potassium chromate filter solutions and a Corning filter plate. Chlorothiazide proved to be more photostable than hydrochlorothiazide and trichloromethiazide in ethanol.
Methanol solutions of hydrochlorothiazide and chlorothiazide were irradiated with fluorescent UV-A lamps in order to simulate degradation under normal conditions. The degradation products were identified by comparison to synthetic standards featuring electrospray ionization mass spectroscopy, ultraviolet spectroscopy, and high performance liquid chromatography. The standards were characterized by high resolution fast atom bombardment MS and 1H NMR. The photolysis of chlorothiazide resulted in photodehalogenation products exclusively, while the irradiation of hydrochlorothiazide primarily yielded photodehalogenation products with significant yields of photodehydrogenation products and minor amounts of thermal hydrolysis products.
A stability-indicating, quality control analysis method was developed and validated for the diuretic drug substances hydrochlorothiazide (HCTZ) and chlorothiazide (CTZ). Micellar electrokinetic capillary chromatography employing the anionic detergent sodium dodecyl sulfate at 30 mM in 20 mM sodium borate buffer pH 9.5 was utilized to separate and quantify the active drug substance HCTZ from CTZ and the common impurity, 4-amino-6-chloro-1,3-benzenedisulfonamide (DSA). A 100 microns I.D. uncoated fused-silica capillary was necessary to provide the sensitivity, i.e. 1 microgram/ml, for quantification of the DSA impurity. In this study, the linearity, precision, selectivity, accuracy, reproducibility and limit of quantitation for the method were investigated for HCTZ, CTZ and DSA. As the first validation of a drug substance method by capillary electrophoresis in this laboratory, unusual care was taken to insure reliability and ruggedness with multiple instruments, capillaries and analysts. Precision and reproducibility in the range of 1% R.S.D. was achieved by controlling subtle injection factors. These included minimizing the time in which the capillary ends were not immersed in buffer or sample during the injection process and minimizing the number of assays for each anode or inlet buffer vial. Stacking induced by differences in ionic strength between sample and capillary buffer was reduced by using a sample buffer concentration similar to that of the capillary buffer. Although stacking accomplished by using lower sample buffer concentrations increased sensitivity, reproducibility was decreased. Achievement of the 1% R.S.D. precision level means that many quality control assays for drugs with good absorbance characteristics can be validated with HPLC reproducibility and CE efficiency. These micellar electrokinetic capillary chromatography methods conform to the USA and European Pharmacopoeial validation guidelines.