Synthesis and Chemistry of Organic Geminal Di- and Triazides.

This review recapitulates all available literature dealing with the synthesis and reactivity of geminal organic di- and triazides. These compound classes are, to a large extent, unexplored despite their promising chemical properties and their simple preparation. In addition, the chemistry of carbonyl diazide (2) and tetraazidomethane (105) is described in separate sections.

Effect of pharmaceutical excipients on the stability of trichlormethiazide tablets under humid conditions.

The stability of trichlormethiazide (TCM) and the drug in the nine products available on the market (the original tablet (B) and 8 generic tablets (G1-G8)) were investigated under humid conditions. TCM was non-hygroscopic and was not degraded under humid conditions. Drug degradation in aqueous ethanol was accelerated with increased water concentration, and the drug stability in buffer solution was improved with decreased pH. TCM decomposition was not detected in each unwrapped tablet at low relative humidity. However, rapid degradation was observed for products G1 and G2, while product B and G7 showed higher stability at high relative humidity. The stability of products G1 and G2 decreased with increasing humidity. The same results were observed for the tablets in press-through packages (PTP), but the degradation rate was much slower than tablets without PTP packages. These results suggested that the adsorbed moisture by excipients cause TCM degradation. Various pharmaceutical excipients are added to TCM tablets and these vary between different pharmaceutical companies. Intact drug and pharmaceutical excipients, including lactose, microcrystalline cellulose, corn starch, hydroxypropylcellulose (HPC), low substituted HPC (L-HPC), calcium stearate, and light anhydrous silicic acid, were mixed, and the sample mixtures were stored in humid conditions. It was found that the TCM content decreased significantly in a binary mixture of TCM/HPC 1 : 1.

Carbonic anhydrase inhibitors. Comparison of chlorthalidone, indapamide, trichloromethiazide, and furosemide X-ray crystal structures in adducts with isozyme II, when several water molecules make the difference.

Thiazide and high ceiling diuretics were recently shown to inhibit all mammalian isoforms of carbonic anhydrase (CA, EC 4.2.1.1) with a very different profile as compared to classical inhibitors, such as acetazolamide, methazolamide, and ethoxzolamide. Some of these structurally related compounds have a very different behavior against the widespread isozyme CA II, with chlorthalidone, trichloromethiazide, and furosemide being efficient inhibitors against CA II (K(I)s of 65-138 nM), whereas indapamide is a much weaker one (K(I) of 2520 nM). Furthermore, some of these diuretics are quite efficient (low nanomolar) inhibitors of other isoforms, for example, chlorthalidone against hCA VB, VII, IX, and XIII; indapamide against CA VII, IX, XII, and XIII, trichloromethiazide against CA VII and IX, and furosemide against CA I and XIV. Examining the four X-ray crystal structures of their CA II adducts, we observed several (2-3) active site water molecules interacting with the chlorthalidone, trichloromethiazide, and furosemide scaffolds which may be responsible for this important difference of activity. Indeed, indapamide bound to CA II has no interactions with active site water molecules. Chlorthalidone bound within the CA II active site is in an enolic (lactimic) tautomeric form, with the enolic OH also participating in two strong hydrogen bonds with Asn67 and a water molecule. The newly evidenced binding modes of these diuretics may be exploited for designing better CA II inhibitors as well as compounds with selectivity/affinity for various isoforms with medicinal chemistry applications.

Interactions of diuretics with a neutral temperature-responsive polymer: study by capillary electroporesis and dynamic light scattering.

Interactions between diuretics and a recently synthesized temperature-responsive neutral copolymer, poly(N-isopropyl acrylamide) (PNIPA) grafted with poly(ethyleneoxide) (PEO) (PNIPA-g-PEO) were investigated by capillary electrophoresis and dynamic light scattering (DLS). At ambient temperatures, the copolymer takes an open, random coil conformation, but above the lower critical solution temperature (LCST), the polymer shrinks and forms large, stable aggregates. Among the diuretics studied, hydrochlorothiazide was detected to bind to PNIPA-g-PEO.

Spectrophotometric studies on the photostability of some thiazide diuretics in ethanolic solution.

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.

First-derivative UV spectrophotometric and high-performance liquid chromatographic analysis of some thiazide diuretics in the presence of their photodecomposition products.

Ethanolic solutions of three thiazide diuretics, chlorothiazide, hydrochlorothiazide and trichlormethiazide, were irradiated with a high-pressure mercury lamp. The products were isolated and their first-derivative UV spectra in ethanol were recorded and compared to those of the parent compounds. The determination of the parent compounds in the presence of the decomposition products was carried out at wavelengths near 220 nm using the zero-crossing technique. Three reversed-phase HPLC methods were also developed for the analysis of the parent compounds. In parallel analyses of the reaction mixtures a good correlation was achieved between these two methods in the determination of hydrochlorothiazide and trichlormethiazide while there was greater variation in the results of chlorothiazide.

Effect of water mobility on drug hydrolysis rates in gelatin gels.

The stability of drugs incorporated in gelatin gels was studied, with a focus on the water mobility in the gels. Trichlormethiazide hydrolysis and kanamycin-catalyzed flomoxef hydrolysis in gelatin gels were chosen as models for apparent first-order and second-order hydrolysis, respectively. The mobility of water in gelatin gels was determined by NMR, ESR, and dielectric relaxation spectroscopies. The amount of bound water in the gels was determined from dielectric relaxation spectra. Spin-lattice relaxation time of water determined by 17O NMR and rotational correlation time of an ESR probe determined by an ESR probing method were useful in determining the microviscosity of the gels. The hydrolysis rate of trichlormethiazide in the gels was found to depend on the amount of free water available for the reaction, while that of flomoxef depended on the microviscosity of the gels, which reflected the mobility of water molecules. Thus the dependence of hydrolysis rates on the water mobility was influenced by the hydrolysis mechanism.