Showing papers by "Juan A. Squella published in 2005"

Recent Developments in the Electrochemistry of Some Nitro Compounds of Biological Significance

Abstract: The redox chemistry of different nitro compounds of biological significance is focused to understand how the reduction of the nitro group can play an active role in several aspects as: electroanalytical determinations, free radical generation and stability and free radical reactivity. We have focused our studies to a lot of pharmaceuticals belonging mainly to the following families: calcium antagonists as nitrobenzene substituted 1,4-dihydropyridines, antibacterial and anti protozoan agents as nitroimidazoles and nitrofurans. The formation of the nitro radical anion as the product of the one electron reduction of nitro compounds generates a series of important consequences passing from chemical to biological aspects. We have used electrochemical techniques to study the formation, stability and reactivity of this nitro radical anion in different media. From cyclic voltammetric experiments it is possible qualitatively to visualize the formation of the nitro radical anion through the one-electron reversible couple due to the redox system nitro / nitro radical anion . Furthermore also is possible the quantitative determination of the kinetic rate constant of the nitro radical anion decay and the interaction constants with other molecules. Although substituents may affect the redox potential and consequently the stability or reactivity of the nitro radical anions, other factors are important in regulation of these properties. Among these factors, it is possible to mention the nature of the reaction media making possible the occurrence of intermolecular reactions of the father-son type between the nitro radical anion and an acidic hydrogen present in the molecules.

Stability study of simvastatin under hydrolytic conditions assessed by liquid chromatography.

Abstract: In this work, a liquid chromatography stability-indicating method was developed and applied to study the hydrolytic behavior of simvastatin in different pH values and temperatures. The selected chromatographic conditions were a C18 column; acetonitrile-28 mM phosphate buffer solution, pH 4 (65 + 35) as the mobile phase; 251 degrees C column temperature; and flow rate 1 mL/min. The developed method exhibited an adequate repeatability and reproducibility (coefficient of variation 0.54 and 0.74%, respectively) and a recovery higher than 98%. Furthermore, the detection and quantification limits were 9.1 x 10(-7) and 2.8 x 10(-6) M, respectively. The degradation of simvastatin fitted to pseudo-first order kinetics. The degradation was pH dependent, being much higher at alkaline pH than at acid pH. Activation energy, kinetic rate constants (k) at different temperatures, the half life (t1/2) and the time for 10% degradation to occur (t90) values are also reported.

Voltammetric Behavior of a 4-Nitroimidazole Derivative Nitro Radical Anion Formation and Stability

Abstract: A new synthesized compound, l-methyl-4-nitro-2-hydroxymethylimidazole (4-MNImOH), was electrochemically reduced at the mercury electrode in aqueous, mixed, and aprotic media. In an aqueous medium, only one voltammetric peak was observed because of the four-electron, four-proton reduction of the nitro group to the hydroxylamine derivative in the 2-12 pH range. For the mixed and nonaqueous media, it was possible to observe a reversible couple due to the first one-electron reduction step of the nitro group to the nitro radical anion.The nitro radical anion decays by a disproportionation reaction in mixed media and by dimerization in a nonaqueous medium. Both disproportionation and dimerization rate constants, k 2 , were determined according to Olmstead's approach, obtaining a value of 1460 ′ 110 M - 1 s - 1 in aprotic medium. In mixed media, the values were dependent both on pH and on the nature of the cosolvent.After comparison of 4-MNImOH with the parent compound, 4-nitroimidazole, we concluded that the substitution with 1-methyl and 2-hydroxymethyl produces a more easily reducible nitro compound and a less stable nitro radical anion than the unsubstituted 4-nitroimidazole. According to the electrochemical results, the 4-MNImOH derivative would be more suitable for enzymatic reduction and less toxic to the host than 4-nitroimidazole.

Assessment of the hydrolytic degradation of lovastatin by hplc

Abstract: In this work an HPLC stability-indicating method was developed and applied to study the hydrolytic behaviour of lovastatin in different simulated fluids. The selected chromatographic conditions were a C-18 column, acetonitrile/methanol/phosphate buffer solution pH 4 (32/33/35) as mobile phase, 45oC temperature column, flux of 1.5 mL/min and UV detection at 238 nm. The developed method exhibited an adequate repeatability and reproducibility (CV 0.057% and 0.73%, respectively) and a recovery higher than 98%. Furthermore, the detection and quantitation limits were 9.1×10-7 M and 2.8×10-6 M. Lovastastin exhibited a pH-dependent degradation with an instantaneous hydrolysis in alkaline media at room temperature. One or two degradation products could be observed when lovastatin is hydrolyzed in alkaline or acid medium, respectively. The degradation products from lovastatin retain the UV-spectra of the parent drug, evidencing that the chromophore structure remains unaltered. Also, lovastatin hydrolysis in different media follows a pseudo first-order kinetic. The rank-order for lovastatin stability in different media was: simulated gastric medium without pepsin > 0.06 M HCl > 0.1 M HCl > phosphate buffer pH 7.4 + sodium laurylsulphate > phosphate buffer pH 7.4

Unexpected diastereotopic behaviour in the H-1 NMR spectrum of 1,4-dihydropyridine derivatives triggered by chiral and prochiral centres

Abstract: 1,4-dihydropyridine derivatives constitute an important pharmacological group for the treatment of cardiovascular diseases. We have synthesised a series 4-(5'-nitro-2'-furyl)-1,4-dihydropyridine derivatives, which were characterised by 1H-NMR. We have found that carboethoxy groups at the C-3 and C-5 on the 1,4-dihydropyridine ring show a much more complex signal in the 1H NMR spectra, either when C-4 is a pseudo-prochiral or a chiral centre.

Nitroradical anion formation from some iodo-substituted nitroimidazoles

Abstract: The electrochemical behavior of iodo nitroimidazole derivatives such as 1-methyl-4-iodo-5-nitroimidazole (M-I-NIm) and 1-methyl-2,4-diiodo-5-nitroimidazole (M-I2-NIm) and the parent compound 1-methyl-5-nitroimidazole (M-NIm), was studied in protic, mixed and non-aqueous media. The electrochemical study was carried out using Differential Pulse Polarography (DPP), Cyclic Voltammetry (CV), Differential Pulse Voltammetry (DPV) and coulometry and as working electrodes mercury and glassy carbon were used. As can be expected, in all media, the effect of introduce iodo as substituent in the nitroimidazole ring produced a decrease of the energy requirements of the nitro group reduction. Certainly, this fact can be explained by the electron withdrawing character of the iodo substituent that acts diminishing the electronic density on the nitro group thus facilitating their reduction. In all the studied media the reduction of M-NIm produced a detectable signal for a nitro radical anion derivative. In the case of M-I-NIm the nitro radical anion was only detectable in both mixed and non-aqueous media. On the other hand the nitro radical anion for the M-I2-NIm was detected only in non-aqueous medium. When glassy carbon electrode was used as the working electrode in a mixed medium a detectable nitro radical anion derivative appeared for all compounds, thus permitting an adequate comparison between them. The obtained values of k2 for M-NIm, M-I-NIm and M-I2-NIm in non-aqueous medium were 5.81×102, 132×102 and 1100×102 M−1 s−1, respectively. From the obtained k2 and t1/2 values in this medium, it is concluded that there is a direct dependence between the presence of iodo substitution in the nitroimidazole ring with the stability of the nitro radical anion.

Electrochemical Study of 4‐Substituted Analogues of Megazol

Abstract: The electrochemical behavior of three different megazol analogues substituted at position 4 and their comparison with the parent compound megazol in protic and aprotic media by cyclic voltammetry, Tast and differential pulse polarography was studied. All the compounds were electrochemically reducible in both media with the reduction of the nitroimidazole group the main voltammetric signal. The one-electron reduction couple due to the nitro radical anion formation was visualized only in aprotic media for all these compounds. By applying cyclic voltammetric methodology we have calculated the dimerization reaction decay constants (k2) of the corresponding nitro radical anions in aprotic media. The nitro radical anion obtained from the synthesized nitroimidazole compound having a bromine substituent in 4-position (GC-141) was significantly more stable than the corresponding radical formed from the compound lacking of the substituent in 4-position, megazol.

Voltammetric behavior of zaleplon and its differential pulse polarographic determination in capsules.

Abstract: In this work both the electrochemical behavior and the analysis of the hypnotic pyrazolopyrimidine derivative zaleplon were studied. Zaleplon in ethanol-0.1M Britton Robinson buffer solution (30-70) showed 2 irreversible, well-defined cathodic responses in the pH range of 2-12 using differential pulse polarography (DPP), tast polarography, and cyclic voltammetry. From chronocoulometric studies, it was possible to conclude that one electron was transferred in each reduction peak or wave. For analytical purposes, the DPP technique working at pH 4.5 for peak I was selected, which exhibited adequate repeatability, reproducibility, and selectivity. The recovery was 99.97 +/- 1.52%, and the detection and quantitation limits were 5.13 x 10(-7)M and 1.11 x 10(-6)M, respectively. The DPP method was applied successfully to the individual assay of capsules in order to verify the content uniformity of zaleplon. Treatment of the sample is not required because the excipients do not interfere, the method is not time consuming, and it is less expensive than column liquid chromatography.