Assessment of the chromatographic lipophilicity of eight cephalosporins on different stationary phases.

The retention behaviors were investigated for a series of eight cephalosporins in thin-layer chromatography (TLC) using stationary phases of RP-2, RP-8, RP-18, NH2, DIOL, and CN chemically bonded silica gel. Additionally, various binary mobile phases (water/methanol and water/acetone) were used in different volume proportions. The retention behavior of the analyzed molecules was defined by RM0 constant. In addition, reversed phase high performance liquid chromatography (RP-HPLC) was performed in lipophilicity studies by using immobilized artificial membrane (IAM) stationary phase. Obtained chromatographic data (RM0 and logk'IAM) were correlated with the lipophilicity, expressed as values of the log calculated (logPcalc) and experimental (logPexp(shake-flask)) partition coefficient. Principal component analysis (PCA) was applied in order to obtain an overview of similarity or dissimilarity among the analyzed compounds. Hierarchical cluster analysis (HCA) was performed to compare the separation characteristics of the applied stationary phases. This study was undertaken to identify the best chromatographic system and chromatographic data processing method to enable the prediction of logP values. A comprehensive chromatographic investigation into the retention of the analyzed cephalosporins revealed a similar behavior on RP-18, RP-8 and CN stationary phases. The weak correlations obtained between experimental and certain computed lipophilicity indices revealed that RM0 and PC1/RM are relevant lipophilicity parameters and the RP-8, CN and RP-18 plates are appropriate stationary phases for lipophilicity investigation, whereas computational approaches still cannot fully replace experimentation.

Hydrolysis of 2,4-dithiophenobarbital.

Hydrolysis of 2,4-dithiophenobarbital in aqueous solutions of pH 2-12 was investigated at 40 and 60 degrees C using UV spectrophotometry. The values of reaction order, rate constants, pKa1 and pKa2 and activation energy were determined. The preliminary estimation of degradation products was accomplished using thin layer chromatography. The major products were isolated by circular chromatography and identified by spectroscopic and classical methods.

The influence of sulfur substituents on the molecular geometry and packing of thio derivatives of N-methylphenobarbital.

The room-temperature crystal structures of four new thio derivatives of N-methylphenobarbital [systematic name: 5-ethyl-1-methyl-5-phenylpyrimidine-2,4,6(1H,3H,5H)-trione], C(13)H(14)N(2)O(3), are compared with the structure of the parent compound. The sulfur substituents in N-methyl-2-thiophenobarbital [5-ethyl-1-methyl-5-phenyl-2-thioxo-1,2-dihydropyrimidine-4,6(3H,5H)-dione], C(13)H(14)N(2)O(2)S, N-methyl-4-thiophenobarbital [5-ethyl-1-methyl-5-phenyl-4-thioxo-3,4-dihydropyrimidine-2,6(1H,5H)-dione], C(13)H(14)N(2)O(2)S, and N-methyl-2,4,6-trithiophenobarbital [5-ethyl-1-methyl-5-phenylpyrimidine-2,4,6(1H,3H,5H)-trithione], C(13)H(14)N(2)S(3), preserve the heterocyclic ring puckering observed for N-methylphenobarbital (a half-chair conformation), whereas in N-methyl-2,4-dithiophenobarbital [5-ethyl-1-methyl-5-phenyl-2,4-dithioxo-1,2,3,4-tetrahydropyrimidine-6(5H)-one], C(13)H(14)N(2)OS(2), significant flattening of the ring was detected. The number and positions of the sulfur substituents influence the packing and hydrogen-bonding patterns of the derivatives. In the cases of the 2-thio, 4-thio and 2,4,6-trithio derivatives, there is a preference for the formation of a ring motif of the R(2)(2)(8) type, which is also a characteristic of N-methylphenobarbital, whereas a C(6) chain forms in the 2,4-dithio derivative. The preferences for hydrogen-bond formation, which follow the sequence of acceptor position 4 > 2 > 6, confirm the differences in the nucleophilic properties of the C atoms of the heterocyclic ring and are consistent with the course of N-methylphenobarbital thionation reactions.

Lipophilicity of thiobarbiturates determined by TLC.

Lipophilicty of 29 thiobarbituric acid derivatives were assessed by reversed-phase thin-layer chromatography using methanol: water mixtures as a mobile phase. A linear relationship was found between RM values and methanol concentrations in the mobile phase. The retention parameter, RM0, was related to theoretical partition coefficients calculated by means of different theoretical procedures (AlogPs, IAlogP, miLogP, logPKowwin, xlogP).

Stability of 2-thiophenobarbital and its N-methyl derivatives in the presence of beta-cyclodextrin.

The rates of hydrolysis of thiophenobarbital and its N-mono- and N,N'-dimethyl-derivatives were determined under different conditions of pH and temperature using UV spectroscopy. They were compared with those obtained in the presence of different concentrations of beta-cyclodextrin. It was found that the compounds degrade with different rates and beta-cyclodextrin retards the hydrolysis. The formation of complexes between the investigated compounds and beta-cyclodextrin was proved by 13C NMR and ROESY spectra and molecular modeling. The inclusion with the phenyl substituent into the beta-cyclodextrin cavity is preferred.