Chemometrical study of the anaesthetical activity of alkoxyphenylcarbamic acid esters.

Several chemometrical techniques were applied to elucidate anaesthetical activity of hydrochlorides of alkoxyphenylcarbamic acid esters. The studied five types of esters contained morpholin-4-ylethyl-, piperidin-1-ylethyl-, piperidin-1-ylpropyl-, azepan-1-ylethyl- and dimethylaminoethyl- groups. The surface anaesthetical activity, designated by A, and the infiltration anaesthetical activity, indicated by B, were correlated to lipophilicity, expressed in different ways--using (a) the logarithm of 1-octanol-water partition coefficient, log P, (b) the logarithm of the HPLC retention factor, log k, (c) the length of the side alkoxy chain represented by the number of carbon atoms, n, (d) molar mass, M. Principal component analysis and cluster analysis were used for close characterization of alkoxyphenylcarbamic acid esters as the potential anaesthetics, and techniques of discrimination analysis were used for predicting the extent of both types of anaesthetic activity. Artificial neural networks were successful in predicting surface anaesthetical activity but prediction of infiltration anaesthetical activity was far less favourable.

[Studies on local anesthetics. Part 183: micellization and thermodynamic parameters of heptacainium chloride in the solution of potassium bromide]. / Stúdium lokálnych anestetik. Cast' 183: micelizácia a termodynamické parametre heptakaíniumchloridu v prostredí roztoku KBr.

The critical micellar concentration (CMC) of the local anaesthetic agent heptacainium chloride in the solution of KBr was determined by the spectrophotometric method in the UV region of the spectrum at the temperature range of t = 20-40 degrees C and pH = 4.5-5.0. The dependence of CMC on the temperature T turned out forming the U-shape with the minimum at the temperature of t = 25 degrees C. The parabolic dependence of CMC on the temperature T was drawn by the fitting of the values using the polynomial function and the so-called power law equation. The CMC dependence on the temperature T was fitted by the second degree polynomial function. The obtained parabolic equations were applied to the "phase separation model", so the following thermodynamic parameters could be calculated: standard Gibbs free energy (deltaG), enthalpy (deltaH degrees), and entropy (deltaS degrees). The thermodynamic parameters were further used to determine the so-called entropy-enthalpy compensation of the systems under study. The compensation temperature was in the following range: (301 +/- 1-303 +/- 3)K. Then the temperature dependence of the enthalpy (deltaH degrees) and entropy (-TdeltaS degrees) contributions to the standard Gibbs free energy (deltaG degrees) for all prepared concentrations of the compound were calculated.

Application of instrumental colour measurement in development and quality control of drugs and pharmaceutical excipients.

This review covers applications of instrumental colour measurement using tristimulus colorimetry in development, stability testing, production and quality control of synthetic and natural drugs, dosage forms and pharmaceutical excipients in the last three decades.

Enantioseparation of chiral sulfoxides using teicoplanine chiral stationary phases and kinetic study of decomposition in human plasma.

Teicoplanin chiral stationary phases (CHIROBIOTIC TAG and CHIROBIOTIC T) used in this study are suitable for enantioseparation of chiral sulfoxides in polar-organic phase mode. The method involves determination of chiral sulfoxides in human plasma on teicoplanin chiral stationary phase after the off-line SPE pre-treatment using OASIS HLB cartridges. The limit of determination was in the range of 0.004-0.026 microg/ml for individual racemic mixtures. The S(+) enantiomeric form eluted always as the first, except the 4-(methyl sulfinyl) biphenyl with less retained R(-) enantiomer. It was found that the rate constants of individual chiral sulfoxides depend on the type of halogen substituent. There was no significant difference in rate constants considering the position of Cl-substitution on aromatic ring of sulfoxides. Moreover, the rate constants of R(-) and S(+) forms of enantiomers are significantly different just in the case of 4-fluoro phenyl sulfoxide.

Applications of molecularly imprinted polymers in analytical and pharmaceutical chemistry.

The paper reviews recent developments in the use of molecularly imprinted polymers in several analytical techniques, such as solid-phase extraction, liquid chromatography, capillary electrophoresis, capillary electrochromatography, and as selective sorbents in chemical sensors. Molecular imprinting is achieved by the interaction between complementary groups in a template molecule and functional monomer units. The benefits of imprinted polymers are low cost, storage stability, high mechanical strength, repeated operations without loss of activity, and potential application to a wide range of target molecules.

HPLC separation of enantiomers using chiral stationary phases.

During recent few years, separations of enantiomers have become one of the most important analytical tasks. Modern separation techniques, such as the chromatographic ones, represent a very powerful tool in this respect and nowadays they are commercially and widely used all over the world. The importance of enantioseparation must be emphasized, not just because of drugs, food additives, and pesticides, but also because of other compounds which affect our life. The use of direct chromatographic enantioseparation seems to be a suitable approach not just in the analytical but also the preparative scale. This paper is focused on the separation of enantiomers using the chiral stationary phase as one of the ways of how to perform direct chromatographic separation.

Influence of alcohols on the critical micelle concentration of heptacainium chloride. Study of local anesthetics, part 171.

The critical micelle concentrations (CMC), of heptacainium chloride in various 0.5 M alcohols (methanol, ethanol and n-propanol) were determined using spectrophotometric measurements. CMC values were determined through the change in the slope when the absorbance versus surfactant concentration was plotted at 234 nm. The CMC values show that micelle formation occurred more easily in methanol than in other higher alcohols.

[Interconversion of stereochemically unstable chiral drugs. Part III: Using beta-cyclodextrin as a chiral stationary phase for HPLC separation of diazepam conformers coupled with an off-line NMR experiment]. / Interkonverzia stereochemicky nestálych chirálnych lieciv. Cast III: Separácia konformérov diazepamu HPLC metodou pouzitim beta-cyklodextrínu ako chirálnej stacionárnej fázy v off-line spojení s NMR experimentom.

Chiral beta-cyclodextrin was used to separate diazepam conformers. Several mobile phases of the composition acetonitrile/acetate buffer 200 mmol/l (pH=3.3, 5.5, 6.5) were employed for this purpose. As follows, the influence of addition of chiral beta-cyclodextrin to the mobile phase on diazepam separation was studied. The interconversion was a concurrence process of separation, resulting from stereolability of the diazepam molecule. The influences of temperature, flow rate, pH, and ionic strength of the mobile phase on interconversion and chromatographic parameters (retention factor and selectivity coefficient) were studied. Complementary off-line NMR measurements were carried out with the goal to confirm the structure of diazepam in the presence of an acid mobile phase.

QSAR study of antimycobacterial activity of quaternary ammonium salts of piperidinylethyl esters of alkoxysubstituted phenylcarbamic acids.

A series of 17 halogenides of quaternary ammonium salts of the alkylpiperidinylethyl esters of 2-pentoxy (and 2-heptoxy) substituted phenylcarbamic acids were evaluated for in vitro antimycobacterial activity against Mycobacterium tuberculosis, M. kansasii, and M. avium. Correlation of this action with lipophilicity (log P, 1-octanol-water system) was used for the description of the structure-antimycobacterial activity relationships (QSARs). The activity increased with the increasing lipophilicity of the compounds.

[Natural derivatives of 4H-pyran-4-one]. / Prírodné deriváty 4h-pyrán-4-ónu.

The present review paper describes the natural derivatives of 4H-pyran-4-one (simple, benzo- and dibenzo-derivatives). It includes their origin, use, and particularly in the case of flavonoids their biological actions and therapeutic use.

[Interconversion of stereochemically unstable chiral drugs: utilization of chromatographic techniques for the study of enantiomerization. Part II: practical applications]. / Interkonverzia stereochemicky nestálych chirálnych lieciv-- vyuzitie chromatografických techník na stúdium enantiomerizácie cast II: praktické aplikácie.

Enantiomerization is a first-order reaction; it means interconversion of one enantiomer into another (and vice versa). This phenomenon is a typical feature of some configurationally unstable chiral compounds and it complicates separation of racemic mixtures. For the study of enantiomerization, chromatographic separation techniques (GC, SFC, CE, MEKC, HPLC) and NMR can be used. Chromatographic methods suitable for investigation of enantiomerization include dynamic chromatography (if time scales of enantiomerization and separation are the same) and stopped-flow chromatography (time scales of both processes are different). The present paper surveys the research of enantiomerization from 1975, when papers describing enantiomerization in greater detail were published, to the present. Today, mathematical approaches and computer-assisted deconvolution procedures are commonly used for evaluation of enantiomerization--calculation of thermodynamic parameters (deltaGapp, deltaHapp, deltaSapp) and rate constants (klapp, k(-1)app). The aim of many publications was not only determination of the enantiomerization energy barrier, but the influence of the chiral stationary phase on enantiomerization was studied as well. In some cases, enantiomerization was used for preparative purposes--a pure enantiomer was obtained and thus complicated synthesis was excluded.

[Interconversion of stereochemically unstable chiral drugs: utilization of chromatographic techniques for the study of enantiomerization, calculation of thermodynamic parameters. Part I: theoretical aspects]. / Interkonverzia stereochemicky nestálych chirálnych lieciv-- vyuzitie chromatografických techník na stúdium enantiomerizácie, výpocet termodynamických parametrov. Cast I.--teoretické aspekty.

The paper explains the theoretical aspects of the process of enantiomerization and describes its characteristic features (generation of a plateau). In addition, some complications are presented that are produced by enantiomerization either from analytical or pharmacological points of view. It also defines the way of how to calculate energy barriers of enantiomerization according to the methods used for the separation of racemic mixtures (stopped-flow or dynamic chromatography). Mathematic models useful in deconvolution of chromatograms are also described. With the use of dynamic methods it is not possible to quantitatively evaluate the obtained chtromatograms and calculate thermodynamic parameters without computer-assisted deconvolution.

[A study of physicochemical properties of 2-, 3-, 4-alkoxyphenylcarbamic acid derivatives with a substituted N-phenylpiperazine moiety in the basic part]. / Stúdium fyzikálno-chemických vlastností derivátov kyseliny 2-, 3-, 4-alkoxyfenylkarbámovej s bázickou castou tvorenou substituovaným N-fenylpiperazínom.

The paper presents the study of some physicochemical properties of 2-, 3-, 4-alkoxyphenylcarbamic acid derivatives with various substituted N-phenylpiperazin-1-yl moiety in the basic part of the molecule. Elemental analysis, melting point, solubility, surface activity, dissociation constant and some lipophilicity parameters i.e.--partition coefficient, capacity factor obtained from HPLC, and R(M) values from reversed-phase thin-layer chromatography were determined.

[HPLC separation of racemic basic esters of alkoxyphenylcarbamic acid using two teicoplanin chiral stationary phases]. / HPLC separácia racemátov bazických esterov alkoxyfenylkarbámovej kyseliny pouzitím dvoch teikoplanínových chirálnych stacionárnych fáz.

This paper presents the results obtained with the use of two chiral stationary phases (CSP), based on a glycopeptide antibiotic agent--teicoplanin aglycone (CHIROBIOTIC TAG) and methylated teicoplanin aglycon m-TAG. Twenty-one racemic mixtures of 1-methyl-2-piperidinoethylesters of 2-, 3- and 4-alkoxyphenylcarbamic acid were examined. The investigation included interaction between separated substances and CSP, and the effect of separation of the enantiomers under study on the value of the resolution factor (R(ij)) under identical chromatographic conditions with the use of the method of high-performance liquid chromatography (HPLC). On the basis of obtained results, it is possible to report that CSP-CHIROBIOTIC TAG is more advantageous for these racemates, because it does not contain a saccharide part, with decrease the possibility of non-polar interactions which exert a negative effect on the R(ij) value.

[Preformulation studies of potential drug XIX M: partition coefficient]. / Predformulacné stúdie potenciálneho lieciva XIX M--rozdel'ovací koeficient.

The factors which markedly influence availability of the drug from the dosage form include also auxiliary substances, which are an inevitable component in the formulation of the drug. In the selection of auxiliary substances for a newly formulated drug, it is necessary to know that the drug is never a simple mixture of mutually independent ingredients, but a dynamic system in which various physical and chemical processes take place. The present paper aims to study the effect of auxiliary substances from the group of humectants with graded concentrations and the effect of the preservative on the partition coefficient of potential drug XIX M. Partition coefficient (P') was estimated in the system n-octanol/aqueous solution with graded concentrations of polyols. In these estimations, n-octanol simulated the horny layer, and the aqueous solution the base of the topical preparation. The auxiliary substances employed were polyols - glycerol, propylene glycol, and sorbitol in 5, 10, 15, and 20% concentrations and an antimicrobially effective solution of Ajatin (Solution benzododecinii bromati) in two concentrations of 0.01 and 0.1 wt %. It follows from the obtained results that the values of partition coefficient of potential drug XIX M are greatly influenced by auxiliary substances. The value of this parameter, and therefore also biological availability, depend not only on the sort of the polyol used and its concentration, but also on the concentration of the preservative employed, in this case Ajatin.

Kinetic study of the degradation of a potential local anesthetic drug in serum using the DNA-based electrochemical biosensor.

DNA-drug association interaction at the DNA modified screen-printed electrode for 1-methyl-2-piperidinoethylester of 2-hexoxyphenylcarbamic acid was found leading to an accumulation of the drug within the DNA layer. A procedure for the determination of drug in blood serum matrix using the protein precipitation and voltammetric measurement of the electroactive drug with the DNA biosensor was obtained and an effort was done to apply it for an assay of the drug enzymatic degradation in human and rabbit sera at 37 degrees C.

[HPLC determination of diperodon enantiomers in blood serum by using teicoplanin chiral stationary phase]. / HPLC stanovenie enantiomérov diperodonu v krvnom sére s pouzitím teikoplaninovej chiralnej stacionárnej fázy.

The chiral stationary phase on the base of teicoplanin and the polar-organic mobile phase methanol/acetonitrile/acetic acid/triethylamine 45/55/0.3/0.2 was used for the separation of diperodon enantiomers. The developed method was suitable to determine the enantiomers in blood serum up to 0.5 microg/ml. The degradation of diperodon enantiomers was studied in serum by an in vitro method and the experimental rate constants were determined.

[Separation of enantiomers of phenylcarbamic acid derivatives by HPLC method]. / Separácia enantiomérov--derivátov kyseliny fenylkarbámovej metódou HPLC.

The chiral stationary phase on the base of beta-cyclodextrin and the mobile phase acetonitrile/0.1 mol/l acetate buffer pH=5.2 (88/12 w/w) were used for the separation of the enantiomers of 1-methoxymethyl, 1-ethoxymethyl, 1-propoxymethyl-2-(1-pyrrolidinyl), (1-piperidino), (1-perhydroazepinyl)ethyl esters of 2-alkoxyphenylcarbamic acid. The influence of the structure of these compounds and the influence of temperature on enantioseparation were studied. The dominant effect on the resolution of enantiomers is exerted by the length of the alkoxysubstituent on the aromatic ring and its position with regard to the stereogenic centre. A decrease in temperature caused an increase in the retention factors of the compounds under study and the resolution values of enantiomers.

A new group of potential antituberculotics: hydrochlorides of piperidinylalkyl esters of alkoxy-substituted phenylcarbamic acids.

A group of 31 of alkoxy-substituted phenylcarbamic acids with the alkoxy group in ortho, meta or para position, and methyl or ethoxymethyl attached to the ethylene moiety in position 1, including both basic ethyl esters and derivatives branched on ethylene, were evaluated for in vitro antimycobacterial activity against Mycobacterium tuberculosis, M. kansasii, and M. avium. To describe the structure-antimycobacterial activity relationships (QSARs), an approach based on a combination of the Free-Wilson analysis was used to express the influence of the substituents on the ethylene group as well as the position of the alkoxy groups on the phenyl ring and of the hydrophobicity of alkyls. In vitro antimycobacterial activity becomes higher with increasing hydrophobic properties of the alkoxy groups. The para- and meta-substituted derivatives were more active than the ortho-substituted ones. Substitution of ethylene in position 1 by methyl increased the activity against M. tuberculosis, a similar substitution by ethoxymethyl increased the activity against M. kansasii. The most active compounds were piperidinyl-1-(ethoxymethyl)ethylesters of heptoxyphenylcarbamic acids.

Selectivity tuning of serially coupled (S,S) Whelk-O 1 and (R,R) Whelk-O 1 columns in HPLC.

The selectivity tuning of two columns coupled in series is investigated in chiral high-performance liquid chromatography. Two columns with reversal enantioselectivities [(R,R) Whelk-O 1 and (S,S) Whelk-O 1] are coupled in series via a T connector. Selectivity of such a column series is tuned by varying the mobile phase flows in the individual columns. The flow ratio necessary for the required selectivity is calculated on the basis of retention factors measured on the individual columns. The performance of this method for adjusting the required selectivity is studied by the separation of enantiomers of alkoxy substituted esters of phenylcarbamic acid. It is demonstrated that the change of the mobile phase flows in the individual columns enables change in the elution order of enantiomers.