Cizmárik J

QSRR models for potential local anaesthetic drugs using high performance liquid chromatography

Quantitative structure-retention relationships (QSRR) were proposed for Separon SGX C18 and Separon SGX Phenyl columns using physico-chemical molecular descriptors for the compounds, which are potential local anaesthetic drugs. Chemometrical methods were used for the QSRR studies of the HPLC retention factor k of 59 esters of alkoxyphenylcarbamic acid, which exhibit surface and/or infiltration anaesthetic activity. Four separation systems were used: phenyl column and acetonitrile/water mobile phase, phenyl column and methanol/water mobile phase, C18 column and acetonitrile/water mobile phase, and C18 column and methanol/water mobile phase. The values of logP and logS and ¹³C and ¹H NMR chemical shifts were simulated and utilized in calculating the corresponding QSRR models and predicting the retention factors by artificial neural networks (ANN). In addition, principal component analysis and cluster analysis were used for a closer characterization of alkoxyphenylcarbamic acid esters. The proposed ANN models, based on optimally selected species descriptors, showed a high degree of correlation between k predicted and k measured. The intercepts and the slopes of the obtained dependences were close to the theoretically expected values of 0 and 1, respectively.

STUDY OF MECHANISM OF ENANTIOSEPARATION. III. THE INFLUENCE OF CARBOHYDRATE MOIETIES OF TEICOPLANIN-BONDED CHIRAL STATIONARY PHASE ON THE SEPARATION OF SOME DERIVATES OF PHENYLCARBAMIC ACID

ABSTRACT Enantiomeric separation of alkoxysubstituted esters of phenylcarbamic acid (local anesthetic drugs) is carried out using high performance liquid chromatography (HPLC) with two chiral stationary phases. The teicoplanin chiral stationary phase—chirobiotic T and the teicoplanin chiral stationary phase without the pendant carbohydrate moieties—chirobiotic teicoplanin aglycone (TAG) were used. The influence of the sugar units, the concentration of the ionic modifiers (diethylamine), the influence of the position and of number of carbon atoms in the analytic alkoxychain substituent, and the composition of the mobile phase; on retention factors and resolution of enantiomers were investigated. By comparison of chromatographic parameters obtained by using both chiral stationary phases, the influence of carbohydrate moieties on the mechanism of chiral separation could be evaluated. The interaction mechanism of the enantiomeric separations is discussed. Better separation, in terms of—greater values of R ij of enantiomers—was achieved with the chirobiotic TAG column.

Is there a place for local anesthetics structurally different from classical amid or ester local anesthetics

Purpose of review The aim of this review is to describe the pharmacology, toxicology and chemistry of the new group of local anesthetics of phenylcarbamic acid type. Recent findings Basic esters of alkoxysubstituted phenylcarbamic acid have shown high local anesthetic potency, while maintaining a relatively safe toxicity profile. Their potency uniquely increases with the decreasing pH of the external medium. This is of importance when using local anesthesics in inflamed tissues, where the action of common local anesthetics is often problematic. Summary The most potent phenylcarbamic anesthetics exceed the potency of the most common clinically used local anesthetics 100–300 times. Due to the unique pH dependency of these local anesthetics, further study of their action is required.

MODIFICATION OF THE CHIRAL BONDING PROPERTIES OF TEICOPLANIN CHIRAL STATIONARY PHASE BY ORGANIC ADDITIVES. HPLC SEPARATION OF ENANTIOMERS OF ALKOXYSUBSTITUTED ESTERS OF PHENYLCARBAMIC ACID

The behaviour of teicoplanin-based chiral stationary phase (CHIROBIOTIC T) towards changes in organic and ionic modifiers in mobile phase was investigated in order to deduce suitable conditions for the liquid chromatographic enantioseparations of a series of alkoxysubstituted esters of phenylcarbamic acid. Methanol and acetonitrile were the non-ionic modifiers tested in the mobile phase, while different aliphatic carboxylic acids (formic acid, acetic acid, propionic acid, hexanoic acid) and bases (triethylamine, trimethylamine, diethylamine) were used as ionic modifiers. The influence of the nature and concentration of the modifiers on retention, selectivity, and resolution of enantiomers was investigated. Under these conditions, enantiomeric separations could be obtained for 3- and 4-alkoxysubstituted derivatives. The elution order of enantiomers was also determined.

Study of the Mechanism of Enantioseparation. IV. Study of Enantioseparation of Some Derivatives of Phenylcarbamic Acid Using π‐Complex Stationary Phase in HPLC

Abstract The Whelk‐O 1 chiral stationary phase (CSP) is an useful column for the high performance liquid chromatographic (HPLC) resolution of enantiomers of 2‐methoxy‐1‐[(4‐methylpiperazino)methyl]ethyl esters of N‐(2‐,3‐, and 4‐alkoxyphenyl)carbamic acid (group of the local anaesthetic drugs) in the polar organic mode and the reversed mode. According to the results of enantiomeric separations in different mobile phases [containing organic modifiers (methanol, acetonitrile, water), with different additives of acetic acid and trimethylamine], it can be postulated that the piperazino part of the phenylcarbamic acid compound is essential because the separation of piperidino, pyrrolidino, and perhydroazepino esters of alkoxy phenylcarbamic acid were not observed. Also the influence of the environment near the analytes stereogenic is important for enantioseparation. A comparison of the enantiomeric elution order and the configuration of the chiral selector shows that R‐(−) enantiomers are more retained on the (R,R) Whelk‐O 1 column and S‐(+) enantiomers are more retained on the (S,S) Whelk‐O 1 column.

HPLC Determination and MS Identification of Dehydroabietic Acid and Abietic Acid in Propolis

Abstract In the present study, the HPLC method on a C18 column with on‐line spectrophotometric and fluorimetric detection was used for separation and determination of dehydroabietic acid and abietic acid in propolis. The samples of propolis tincture were prepared prior to the HPLC analysis. The mobile phase for isocratic elution was methanol‐water 87:13 containing 0.05% formic acid. Abietic acid was detected with spectrophotometric detection at 238 nm, and dehydroabietic acid was detected with fluorimetric detection (excitation 225 nm, emission 285 nm). The limits of determination (signal/noise ratio 10) were 100 ng/mL for dehydroabietic acid and 200 ng/mL abietic acid. The calibration graphs were linear over a wide interval from the limit of determination to 1 mg/mL. Analytical recovery and reproducibility exceeded more than 89%. The developed method was used for analysis of propolis from Slovakia. Mass spectrometry was used for identification of the studied acids. The results demonstrated that dehydroabietic acid was present in all tested samples of propolis. Its content was different (3.7 µg/g–44.7 µg/g of propolis) depending on the source of propolis.

STUDY OF LOCAL ANAESTHETICS. CLVIII. CHROMATOGRAPHIC SEPARATION OF SOME DERIVATIVES OF SUBSTITUTED PHENYLCARBAMIC ACID ON A VANCOMYCIN-BASED STATIONARY PHASE

Vancomycin, immobilized on silica, served as the chiral stationary phase (CSP) in this investigation with a polar organic solvent as the mobile phase in high performance liquid chromatography (HPLC). Enantiomers of alkoxysubstituted esters of phenylcarbamic acid (local anaesthetic drugs) were examined in order to evaluate the enantiorecognition process. The chromatographic behavior was investigated in order to obtain a deeper insight into the enantiodiscrimination process. A variety of factors, including the nature and concentration of the ionic modifiers in the mobile phase were examined. Conditions for the enantioseparation of derivatives of phenylcarbamic acid were found. The interaction mechanism of the separations is discussed.

STUDY OF MECHANISM OF ENANTIOSEPARATION. II. HPLC CHIRAL ANALYSIS OF ALKOXYSUBSTITUTED ESTERS OF PHENYLCARBAMIC ACID

ABSTRACT The chromatographic separation of enantiomers of a series of 2-alkoxysubstituted esters of phenylcarbamic acid (C1−C10) were studied on (β- and γ-) cyclodextrin chiral stationary phases. The pH and concentration of organic modifier in the mobile phase were optimized. It was observed that the chromatographic performance of basic compounds could be strongly enhanced by increasing the pH of the mobile phase. Increasing the pH produced higher values for the enantiomeric resolution and the retention factors. This work demonstrated that the nonpolar interactions between the chiral stationary phase and the neutral molecules of these enantiomers had the greatest effect on enantioresolution.