Photodegradation and Photostability Studies of Bendroflumethiazide in Pharmaceutical Formulations and Urine Samples by Micellar Liquid Chromatography

Address correspondence to S. Carda Broch. endroflumethiazide (BMFT [RS]-3-phenylmethyl-3,4-dihydro-6-trif luoromethyl-2H1,2,4-benzothiadiazine-7-sulfonamide-1,1dioxide) is a potent diuretic drug extensively used for the treatment of hypertension and oedema that belongs to the thiazide family (1). BMFT is well absorbed from the gastrointestinal tract after oral administration and the absorption is not affected by food. It lowers blood pressure and removes extra salt and water from the body by acting on the kidneys. BFMT is usually prescribed as tablets and frequently in combination with b-blockers. Because of the increase in urine flow, which reduces body weight, the administration of BFMT is forbidden in sports where the competition is based on weight classes (2). Because of the diluting effect, intake of such drugs could also result in suppression of other doping substances below their limits of detection. BFMT hydrolyzes to 5-trifluoromethyl2,4-disufhoamoyl-aniline (TFSA) and phenylacetaldehyde in acidic media at high temperature. Under certain conditions, BFMT has also been reported to produce the thiazide diuretic hydroflumethiazide (HFMT, 3,4-dihydro-6-trifluoromethyl2H-1,2,4-benzothiadiazine-7-sulfonamide1,1-dioxide) (3,4). HFMT is formed by the reaction of TFSA with formaldehyde, which is a degradation product of the polymers polyethylene glycol 6000 and poloxamer 188. High humidity promotes this reaction. Rapid and reliable methods are required for drug monitoring in therapeutic and doping control. Different procedures including amperometric and conductimetric titrimetries (5), polarography (6), capillary electrophoresis (7), electrochromatography (8), and chromatographic techniques, such as thin-layer chromatography with fluorescence scanning (9,10), reversed-phase liquid chromatography (1,3,11,12), and gas chromatography (13,14) with either ultraviolet (UV) or fluorescence detection, have been described to measure BFMT alone or with other compounds. Several authors have also investigated the stability of BFMT and the kinetics of the degradation process in aqueous, methanolic, and polymeric solutions (3,4,15,16). Barnes and Nash have studied the stability of BFMT in capsules (17,18). However, degradation processes in physiological samples (urine, serum, or plasma) and the possibility of photochemical degradation, very common in the group of thiazide diuretics, are rarely mentioned in analytical reports. This may limit their usefulness in the therapeutic monitoring of BFMT at the levels found in patients and also in pharmacokinetic bioequivalence studies. The comments found in the literature about the adequate medium to prepare BFMT solutions are not convincing. In this work, the experimental conditions needed to prevent the degradation of this diuretic, induced by different pathways, in the analytical laboratory are studied. When a sportsman deliberately takes BFMT, it is possible that the drug remains undetected if adequate precautions are not taken. A simple, rapid and selective chromatographic procedure that uses a micellar mobile phase of sodium dodecyl sulfate is described and applied to the control of some A simple HPLC procedure is described for the determination of bendroflumethiazide (BMFT) in pharmaceutical formulations and urine samples. No interferences from common additives or other drugs frequently administered with BMFT or from endogenous compounds in urine samples were found. The lack of an organic solvent in the mobile phase reduces the risk of environmental contamination and human toxicity.