Structural and physicochemical profiling of morphine and related compounds of therapeutic interest.

A concise account of the physicochemical properties of morphine and its derivatives of therapeutic interest is provided. Such properties include macroscopic and microscopic acid/base parameters, lipophilicity, solubility, permeability that all influence the fate of drugs in the body. The dependence of these parameters on pH is discussed and subsequent implications in drug administration and formulation are presented.

Capillary electrophoresis separation of vinpocetine and related compounds: prediction of electrophoretic mobilities in partly aqueous media.

Offord's equation, a relationship between electrophoretic mobility and charge, size and shape of peptides, has been extended to quantitate the electrophoretic mobility of vinca alkaloids. Partly aqueous protonation constants and the derived theoretical mobilities have been proven to be able to predict experimental electrophoretic mobilities. In practice, seven vincamine derivatives of very low water-solubility were separated by capillary electrophoresis. Buffer total concentration, apparent pH and methanol content, the three most important parameters of the running buffer, were used in triangular resolution mapping to characterize separation. Even though electrophoresis is well known to slow down in partly aqueous media, under our optimized circumstances a baseline separation was achieved within 8 min in each case.

Proton speciation and microspeciation of vinpocetine and related compounds in aqueous and biomimetic media.

PURPOSE: The determination of protonation macroconstants of twelve compounds in the vincamine drug family and the determination of protonation microconstants of cis- and trans-apovincaminic acid in media of various solvent composition to characterise their site-specific basicity and to estimate the concentration of the membrane-penetrating and receptor-binding forms. METHODS: UV-pH titrations have been used to determine the protonation macroconstants in 10-43 wt% methanol/water mixtures. Yasuda-Shedlovsky extrapolation was applied to obtain aqueous logK values for compounds sparingly soluble in water. Protonation microconstants were also determined by deductive methods for compounds of free carboxylic group. RESULTS: In the case of the two water-soluble compounds the extrapolated and the directly measured aqueous logK values were in good agreement, verifying all other extrapolated data. Compounds of cis-D/E ring anellation are 0.4-0.8 logK units more basic than their epimeric, trans counterparts. The pH-dependent distribution of apovin-caminic acid microspecies in aqueous and membrane-like media is depicted in microspeciation diagrams. CONCLUSIONS: The N(4) nitrogen is more shielded by the adjacent ethyl group in trans-D/E ring anellation eburnanes than in cis ones, as reflected by the protonation constants. Solvent-dependent basicity data predict superiority of trans isomers in lipophilicity and membrane-penetrating ability.

[Microequilibrium of drug molecules]. / Gyógyszervegyületek mikroegyensúlyai.

Protonation macro-, micro-, and submicro constants are physico-chemical parameters of crucial importance, concerning the fate of bio-, drug, and narcotic drug molecules in the body and in protic solvents. The most important characteristics, relationships, applications and biological significance of these parameters are reviewed, using acetylcysteine and cysteine, as examples. The mucolytic effect of acetylcysteine, an active principle in numerous drugs, is interpreted in terms of protonation state of the molecule and its thiolate site. Microscopic protonation constants of acetylcysteine, data that have not previously appeared, are also reported.