Kinetics and mechanism of degradation of klerval, a pseudo-tetrapeptide.

The degradation of klerval (I) was studied as a function of pH. The extent and routes of degradation were found to be pH-dependent. Under strongly acidic conditions (pH<2), the drug predominantly undergoes specific acid-catalyzed hydrolysis of the side-chain amide bond yielding II8), the drug undergoes specific base-catalyzed hyrolysis yielding II and epimerization generating D-epimer. The epimerization appears to occur via the succinimide intermediate in neutral pH region. With increasing pH, however, the epimerization rate increases due to direct epimerization of the peptides.

Epimerization and hydrolysis of dalvastatin, a new hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor.

In aqueous solutions, dalvastatin (1) undergoes epimerization as well as hydrolysis. The transformation of the drug was studied as a function of pH at 25 degrees C in aqueous solutions containing 20% acetonitrile. At all pH values, first-order plots for the conversion are biphasic, indicating rapid equilibration of 1 with its epimer (2) and slower hydrolysis of 1 to the corresponding beta-hydroxy acid (3). Apparent first-order rate constants for the biexponential equation are given as a function of pH. The alkyl-oxygen cleavage of the lactone ring results in the epimerization of 1 to 2, whereas the acyl-oxygen cleavage results in the hydrolysis of 1 to 3. The epimerization is an SN1 reaction reaching an equilibrium of [1]eq/[2]eq = 1.27. The epimerization rate is increased with an increase in the water content of the solvent. The hydrolysis of 1 to 3 is acid and base catalyzed. The hydrolysis is reversible in acidic media and irreversible in neutral and basic media. At pH values greater than 9, the hydrolysis reaction proceeds more rapidly than the epimerization.

Kinetics of degradation of levothyroxine in aqueous solution and in solid state.

The kinetics of the deiodination of levothyroxine in aqueous solution were studied over the pH range 1 to 12. Temperature dependence of the reaction was also studied. The log k - pH profile indicated that the kinetics of deiodination include proton attack on the anion and dianion in acidic solution and water attack on the anion and dianion in alkaline solution. A possible mechanism of the deiodination was discussed. The solid-state stability of levothyroxine sodium was studied at elevated temperatures; and the compound was found to undergo deamination on heating. The decomposition follows biphasic first-order kinetics, with the most rapid decomposition occurring at the beginning of heating.

Novel method of derivatization of an amidinourea (lidamidine) for GLC analysis.

A new quantitative GLC method for analysis of lidamidine hydrochloride (I) was developed. The method was based on derivatization of I to 1-(2,6-dimethylphenyl)-4-methylamino-dihydro-1,3,5-triazin-2-one (II) using dimethylformamide dimethylacetal reagent. Compound II was synthesized and characterized by IR, NMR, mass spectrometry, and elemental analysis. The assigned structure was in agreement with characterization analyses. Cyclization of I to a triazinone using dimethylformamide dimethylacetal reagent presented a new route for the preparation of II.

Analytical-physical profile of lidamidine hydrochloride (WHR-1142A), a novel antidiarrheal agent.

The structure elucidation, physical and chemical parameters and hydrolysis kinetics of 1-(2,6-dimethylphenyl)-3-methylamidinourea hydrochloride (WHR-1142 A, lidamidine hydrochloride), a novel antidiarrheal agent, were determined. The stability of the substance in aqueous solution (pH 1-13) was studied at 50 degrees, 65 degrees and 80 degrees C.

Kinetics of hydrolysis of fenclorac.

The kinetics of hydrolysis of fenclorac were studied to determine its stability in aqueous solution at different pH's and temperatures. For this study, a stability-specific liquid chromatographic assay method was developed to separate fenclorac from its hydrolysis product, alpha-hydroxy-3-chloro-4-cyclohexylbenzeneacetic acid. The k-pH profile in the 0-12 pH range in various buffer solutions shows that fenclorac is stable in its undissociated form in strongly acidic media and is unstable in neutral and alkaline media. The instability of fenclorac in aqueous solution is proportional to the degree of ionization of the carboxyl group in the 1-4 pH range and is independent of pH above 4. The rate-determining step in the mechanism of hydrolysis of fenclorac involves ionization of the carbon-chlorine bond. The ionization is catalyzed by an intramolecular necleophilic attack on the alpha-carbon by the dissociated carboxyl group, resulting in the formation of an unstable intermediate, a three-membered ring lactone. This unstable intermediate rapidly hydrolyzes to the final hydrolysis product. This mechanism is supported by experimental evidence such as the medium effect, positive salt effect, common ion effect, and substituent effect. Arrhenius parameters for the hydrolysis of fenclorac and its 3-nitro substituted analog were obtained.

Effect of novobiocin and its combination with tetracycline, chloramphenicol, erythromycin, and lincomycin on the microbial generation of Escherichia coli.

Inhibition of the steady-state generation of Escherichia coli by the bacteriostatic antibiotic novobiocin is linearly related to drug concentration in the range of 0 to 30 mug/ml. Increased cell sizes result because the drug inhibits cell division. The generation rate dependence on drug concentration depends on the nonionized fraction of novobiocin and is invariant with inoculum size or medium composition. However, the antibacterial activity of novobiocin decreases as the concentration of nutrients and Mg(2+) increases, although the inhibitory action of novobiocin on generation rate remains unchanged for concentrations of Mg(2+) above 8.1 x 10(-4) M. Novobiocin is synergistic in combinations with tetracycline in broth, but not when the Mg(2+) was maintained at 4.05 x 10(-3) M. Combinations of novobiocin with the 50S ribosomal subunit inhibitors chloramphenicol, erythromycin, or lincomycin are antagonistic, and the degree of growth inhibition is determined only by that component of the binary combination that would have the greater potency if it were acting alone.