Abstract
The kinetics of indomethacin (IM) degradation was examined in alkaline aqueous solutions (pH 7.0-10.0) at various temperatures for the purpose of prediction of IM stability. The pseudo first-order rate constants (kobs) were evaluated from log absorbance of IM versus time plots at 320nm. The kobs was independent of borate buffer concentration but the primary salt effect was positive, suggesting the reaction of the same kind of ions plays a role in the mechanism of IM hydrolysis. The reaction was specific base catalyzed. From the data at 40, 50, 60 and 70°C, the microscopic rate constants (kOH-) for hydrolysis were determined and their thermodynamic parameters were obtained from Arrhenius-type plot at μ=0.5. The effect of organic solvents, propylene glycol, polyethylene glycol 400 (PEG 400) and glycerin on the rate constants were also investigated for the degradation of IM in phosphate buffer solutions (pH 8.0, μ=0.5) at 60°C. Degradation reaction obeyed pseudo first-order kinetics in the presence of the solvents. The values of kobs were decreased with increase in propylene glycol or PEG 400 concentration. The estimated half-lives at 60°C and pH 8.0 were 5.1, 7.1 and 11.9 hr in water or 20% aqueous solutions of propylene glycol or PEG 400, respectively.These stabilizing effects could be associated with the decrease in dielectric constant of the reaction medium.In the case of glycerin-water mixtures, unexpectedly, hydrolysis of IM was accelerated by increase in glycerin concentration and the half-life was 1.7 hr in 20% solution. The mechanism of the destructive action of glycerin on IM has not yet known, this result suggests that glycerin may influence the stability of IM pharmaceuticals in which glycerin is contained as a humectant or excipient.
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