Chiral ligand-exchange chromatography for diastereo-enantio separation of exametazime

The diastereo-enantio separation of isomeric mixtures of exametazime (HM-PAO) by liquid chromatography is described using an achiral sorbent (RP-18). A chiral eluent with the initial complex of Cu(II) and the optically active selector N,N-dimethyl-l-phenylalanine (l-DM-PhA), based on the ligand-exchange principle, has been applied. The separation is based on the presence of the immobilized binary complex Cu(l-DM-PhA

Chiral ligand-exchange chromatography as the screening method for proposed modifications in exametazime synthesis to enhance diastereoselectivity

Tc-99m(V)-d,l-HM-PAO complex is well-known radiopharmaceutical for regional cerebral blood flow imaging. The proposed modifications in exametazime, hexamethylpropyleneamine oxime (HM-PAO) (4,8-diaza-3,6,6,9-tetramethylundecane-2,10-dione bisoxime) synthesis, for reduction of intermediary reactant diiminebisoxime (DI) (4,8-diaza-3,6,6,9-tetramethylundecane-3,8-diene-2,10-dione bisoxime) concerned two reductants (NaBH4 and KBH4), two solvents (ethanol and 2-propanol), and three mole ratios of reactant/reductants (1:1, 1:1.5, and 1:2). The simultaneous analysis of diastereo-enantiomeric HM-PAO content, as well as the content of starting DI, in different reduction mixtures were pet-formed using chiral ligand-exchange chromatography (CLEC). The separation of the samples of investigated reduction mixtures, obtained in the second step of HM-PAO synthesis, has been accomplished by using an achiral sorbent (RP- 18) and a chiral mobile phase (CMP) containing copper(II) complex with N,N-ditnethyl-L-phenylalanine (L-DM-PhA) as initial complex for CLEC. With 12 different reduction conditions, the obtained ratios of diastereoisomers d,l-HM-PAO: mesa-HM-PAO varied from 69.2:30.8 to 15.9:84.1, in comparison to the reduction in routine synthesis of HM-PAO which gives an equal mixture of diastereoisomers. The ternary mixed complexes formation recorded spectrophotometrically on addition of HM-PAO or DI to the mobile phase with binary complex Cu(L-DM-PhA)(2), due to the evidence of bathochromic shift of 46 nm for lambda(max) with significant difference in absorptivity contributes to separation mechanism. (C) 2003 Elsevier B.V. All rights reserved

UV derivative spectrophotometric study of the photochemical degradation of nisoldipine

The photodecomposition of nisoldipine ((+/-)3-isobutyl-5-methyl-1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylate), whereby its 4-(2-nitrosophenyl) pyridine analogue is obtained as the photolytic product, was investigated under daylight exposure by means of UV derivative spectrophotometry. The optimal instrumental parameters (120 nm/min scan speed: 2 nm slit width; Delta lambda = 10 nm and 5 s response time) for analogue derivative spectra were established for amplitudes D-1(285) and D-2(291) (measured to the baseline) of the nitroso analogue assay, as well as for D-1(386) of the parent compound-nisoldipine assay. Using the first-order derivative spectrum, the minimum detectable amount of nitroso analogue in the presence of nisoldipine was equivalent to an impurity level of 5% and by the second-order derivative spectrum, the determination limit was equivalent to an impurity level of 2%. The degradation of nisoldipine followed within 30 days and the calculated maximal degradation rate was 1.6% per day for nisoldipine raw material, but significantly lower values of 0.19 and 0.15% per day were obtained for Nisoldin(R) tablets (10 and 5 mg, respectively). (C) 2000 Elsevier Science S.A. All rights reserved

The Role of l-arginine in Inclusion Complexes of Omeprazole with Cyclodextrins

In this study, we investigate how the effect of l-arginine (ARG) and cyclodextrins upon omeprazole (OME) stability and solubility. The effect of the presence of ARG on the apparent stability constants (K1:1) of the inclusion complexes formed between OME and each cyclodextrin, β-cyclodextrin (βCD), and methyl-β-cyclodextrin (MβCD) is studied by phase solubility diagrams and nuclear magnetic resonance (NMR) spectroscopy. The interaction of OME with those cyclodextrins, in the presence of ARG, is characterized using NMR spectroscopy and molecular dynamics simulations. ARG significantly increases the drug solubility and complex stability, in comparison to inclusion complexes formed in its absence. The effect is more pronounced for the OME:βCD complex. ARG also contributes to a larger stability of OME when free in aqueous solution. The combination of ARG with cyclodextrins can represent an important tool to develop stable drug formulations

A Comprehensive Development Strategy in Buccal Drug Delivery

This work combines several methods in an integrated strategy to develop a matrix for buccal administration. For this purpose, tablets containing selected mucoadhesive polymers loaded with a model drug (omeprazole), free or in a complexed form with cyclodextrins, and in the absence and presence of alkali agents were subjected to a battery of tests. Mucoadhesion studies, including simple factorial analysis, in vitro release studies with both model-dependent and model-independent analysis, and permeation studies were performed. Mucoadhesive profiles indicated that the presence of the drug decreases the mucoadhesion profile, probably due its hydrophobic character. In tablets loaded with the drug complexed with β-cyclodextrin or methyl-β-cyclodextrin, better results were obtained with the methylated derivative. This effect was attributed to the fact that in the case of β-cyclodextrin, more hydroxyl groups are available to interact with the mucoadhesive polymers, thus decreasing the mucoadhesion performance. The same result was observed in presence of the alkali agent (l-arginine), in this case due to the excessive hydrophilic character of l-arginine. Drug release from tablets was also evaluated, and results suggested that the dissolution profile with best characteristics was observed in the matrix loaded with omeprazole complexed with methyl-β-cyclodextrin in the presence of l-arginine. Several mathematical models were applied to the dissolution curves, indicating that the release of the drug, in free or in complexed state, from the mucoadhesive matrices followed a super case II transport, as established on the basis of the Korsmeyer–Peppas function. The feasibility of drug buccal administration was assessed by permeation experiments on porcine buccal mucosa. The amount of drug permeated from mucoadhesive tablets presented a maximum value for the system containing drug complexed with the methylated cyclodextrin derivative in presence of l-arginine. According to these results, the system containing the selected polymer mixture and the drug complexed with methyl-β-cyclodextrin in presence of l-arginine showed a great potential as a buccal drug delivery formulation, in which a good compromise among mucoadhesion, dissolution, and permeation properties was achieved