Mihalj Posa

In this paper, bile acids' retention parameter, R(M), obtained in normal phase thin-layer chromatography is determined as a function of the temperature (293-323 K). Analyzed bile acids belong to congeneric group with two oxygen atoms (OH or oxo groups) on the steroid core and congeneric group with three oxygen atoms. For molecules of both congeneric groups it is found that there is a linear relationship between R(M) and temperature, therefore R(M) decreases with the increase of temperature. In certain congeneric groups, parameters of linear function (R(M) - T) can be linked to the structural characteristics of bile acids, firstly with their spatial orientation (steric position in relation to the steroid mean plane) of the steroid oxygen atom (OH or oxo groups). Absolute values of slope (see text for symbol) of linear function (R(M) - T) increase if steroid oxygen atoms are not in the polar plane, since then the possibility of forming hydrogen bonds with stationary phase decrease...

ABSTRACT The aim of this study was to investigate micellar and self-assembly properties of four sodium salts of naphthenic acid mixtures by determination and comparative analysis of their critical micelle concentration values at seven different temperatures ranging from 10 to 40 °C using spectrofluorophotometric measurements. It was concluded that fractions having the lowest percentage of aliphatic structures give the least flexible micelles due to sterically rigid structure of cyclic side chains, what makes them difficult to pack in the micellar core. Additionally, surface properties of aqueous solutions of investigated mixtures were studied by the determination of the maximum surface excess, Γ max and the minimum area per surfactant molecule (A min) values.

... bis(dimethylcetylammonium bromide), J. Colloid. Interface. Sci. 359 (2011) 467-473. [7] M. JahirulIslam, MMR Choundri, SMF Shahed, MA Subhan, Effect of some biologically important organic compounds on the micellar properties of sodium dodecyl sulphate, Proc. Pak. Acad. ...

Bile salts are steroidal biosurfactants. Micellar systems of bile salts are not only important for solubilisation of cholesterol, but they interact with certain drugs changing thus their bioavailability. The number-average aggregation numbers (n¯) are determined using Moroi-Matsuoka-Sugioka thermodynamic method. Critical micellar concentrations were determined by spectrofluorometric method using pyren and by surface tension measurements. Micelles of ethylidene derivatives posess folowing values for n¯: 7-Eth-D (n¯=11 (50mM) - n¯=14.8 (100mM); 12-Ox-7-Eth-L (n¯≈8.8, without concentration dependence) and 7,12-diOx-3-Eth-Ch (n¯≈2.9,without concentration dependence). In the planes n¯ - ln k and ln CMC - ln k derivative 7-Eth-D is outlier in respect to hydrophobic linear congeneric groups. Gibbs energy of formation for 7-Eth-D anion micelles in adition to the Gibbs energy of hydrophobic interactions consist excess Gibbs energy (G(E)) from hydrogen bond formation between building blocks o...

Retention coefficients (k) of cholic acid and its keto derivatives are determined by means of Reversed Phase High Pressure Liquid Chromatography at different temperatures (303K, 309K, and 313K). At each studied temperature, retention factor decreases if the hydroxyl group in the cholic acid molecule replaces oxo group. In addition, the change of retention coefficient in a function of temperature (Δk/ΔT) is dominant for the cholic acid while by increasing the number of oxo groups it decreases. Introduction of an oxo group in a bile acid molecule leads to the lower hydrophobicity of the β side of the steroid nucleus. Because of that, less interaction happens between β side of the steroid nucleus and stationary phase. For dehydrocholic acid (three- oxo derivative), the value for Δk/ΔT shows an exception of this explanation. This suggests that in this molecule the planar polarity is disturbed. Partition coefficient K of nitrazepam (probe molecule) in micelles of bile acid salts at the e...

Different multiple regression methods including forward stepwise multiple linear regression (MLR), principal component regression (PCR) and partial least squares (PLS) have been applied to the modeling of partition coefficient (lipophilicity) of bile acids and their derivatives by means of 16 different descriptors obtained by using Alchemy package software and retention index R(Mo) as an experimental estimation of lipophilicity. Retention indices for bile acids and their derivatives were determined by reversed phase high-performance thin layer chromatography on RP-18 W bounded stationary phase with methanol-water in different volume proportions as mobile phase. The results achieved concerning the prediction of Log P are highly significant and consistent with the molecular structure of the compounds investigated. The sum of absolute values of the charges on each atom of the molecule, in electrons (SQ), the sum of absolute values of the charges on the nitrogens and oxygens in the molecule, in electrons (SQ(NO)), specific polarizability of a molecule (SP), the third-order connectivity index ((3)chi) and molecular lipophilicity, seem to be dominant in the partition mechanism. In addition, regression models developed have allowed a correct estimation of the partition coefficients of cholic acid (Log P(HA)=2.93; Log P(A)(-)=2.02) as compared with reported experimental values (Log P(HA)=2.02; Log P(A)(-)=1.1).

ABSTRACT Purpose: To evaluate the predictive performance of phenytoin multiple dosing non-linear pharmacokinetic model in rabbits for possible application in therapy individualization in humans.Methods: Phenytoin was intravenously administered to 10 rabbits (2 – 3 kg). Plasma concentrations were measured by high pressure liquid chromatography (HPLC). Rabbits received 3 single phenytoin doses (11, 22 and 44 mg/kg) and plasma concentrations were fitted according to linear twocompartmental model. In all the rabbits, based on 3 different multiple doses (D1, D2, D3, range 9 – 15 mg/kg), 3 steady state plasma concentrations (Css1, Css2, Css3, range 20 - 56mg/l) were achieved. Formultiple dosage, the non-linear parameters, Km and Vm, were calculated according to the equations: Km = (D1-D2)/[(D2/Css2)-(D1/Css1)] and Vm = D2+KmD2/Css2, and individually used to calculate Css3 = D3Km/(Vm-D3). Predicted and measured Css3 values were compared.Results: The values for pharmacokinetic parameters after single doses were dose-dependent. The pronounced inter-individual variations in Km (extreme values 18 – 91 mg/l differed 5.5 times) and Vm (11 – 28 mg/kg/h) values were recorded. Significant correlation of predicted Css3 with the measured value for the same dose (D3) was found (r = 0.854, N = 10, p < 0.01). There was no statistical difference between predicted and measured concentrations (t-dependent test = 1.074, p < 0.05).Conclusion: Non-linear parameters, Km and Vm, obtained from only two steady-state concentration measurements can be successfully used to compute and achieve a particular steady-state plasma concentration and optimal dosage regimen.

Micellisation process for sodium dodecyl sulphate and sodium cholate in 1∶1 molar ratio was investigated in a combined approach, including several experimental methods and coarse grained molecular dynamics simulation. The critical micelle concentration (cmc) of mixed micelle was determined by spectrofluorimetric and surface tension measurements in the temperature range of 0-50°C and the values obtained agreed with each other within the statistical error of the measurements. In range of 0-25°C the cmc values obtained are temperature independent while cmc values were increased at higher temperature, which can be explained by the intensive motion of the monomers due to increased temperature. The evidence of existing synergistic effect among different constituent units of the micelle is indicated clearly by the interaction parameter (β1,2) calculated from cmc values according to Rubingh. As the results of the conductivity measurements showed the negative surface charges of the SDS-NaCA ...

Linear dependence between temperature (t) and retention coefficient (k, reversed phase HPLC) of bile acids is obtained. Parameters (a, intercept and b, slope) of the linear function k=f(t) highly correlate with bile acids' structures. Investigated bile acids form linear congeneric groups on a principal component (calculated from k=f(t)) score plot that are in accordance with conformations of the hydroxyl and oxo groups in a bile acid steroid skeleton. Partition coefficient (K(p)) of nitrazepam in bile acids' micelles is investigated. Nitrazepam molecules incorporated in micelles show modified bioavailability (depo effect, higher permeability, etc.). Using multiple linear regression method QSAR models of nitrazepams' partition coefficient, K(p) are derived on the temperatures of 25°C and 37°C. For deriving linear regression models on both temperatures experimentally obtained lipophilicity parameters are included (PC1 from data k=f(t)) and in silico descriptors of the shape of a molecule while on the higher temperature molecular polarisation is introduced. This indicates the fact that the incorporation mechanism of nitrazepam in BA micelles changes on the higher temperatures. QSAR models are derived using partial least squares method as well. Experimental parameters k=f(t) are shown to be significant predictive variables. Both QSAR models are validated using cross validation and internal validation method. PLS models have slightly higher predictive capability than MLR models.

This study presents application of a new linear and nonlinear fractional derivative two compartmental model to the evaluation of individual pharmacokinetics. In the model, the integer order derivatives are replaced by derivatives of real order. A specific nonlinear function is used for the fit improvement of a fractional derivative two compartmental model with the mass balance conservation. The agreement of the values predicted by the proposed model with the values obtained through experiments with bumetanide tablets in human volunteers is shown to be good. Thus, pharmacokinetics of bumetanide can be described well by a linear or a nonlinear two compartmental model with fractional derivatives of the same order proposed here. Parameters in the model are determined by the least squares method and the particle swarm optimization numerical procedure is used. The results show that the linear fractional order two compartmental model for bumetanide is useful improvement of the classical (integer order) two compartmental model and that the nonlinear fractional order model is useful improvement of the linear model in a great number of volunteers.

The objective of this study was to understand the prolonged analgesic action of morphine hydrochloride observed in the presence of sodium 12-oxochenodeoxycholanate. Based on literature, this phenomenon may be due to the formation of aggregates in the cell between the molecules of bile acids and morphine. In addition to the sodium 12-oxochenodeoxycholanate, the present investigation also included salts of cholic and 7-oxodeoxycholic acids. Saturation transfer difference NMR experiments showed that morphine binds to the bile acid molecule close to the aromatic protons H1 and H2 provided that the concentration of the bile acid salt approaches the critical micellar concentration (CMC). The spin-lattice relaxation times (T(1)) of the affected protons decrease significantly in the presence of micellar solutions of the bile acid salts, and the most pronounced change in T(1) was observed for sodium 7-oxodeoxycholate. Diffusion-ordered NMR experiments suggested that morphine hydrochloride can interact only with sodium 7-oxochenodeoxycholate. It can be supposed that the molecular ratio of sodium 7-oxodeoxycholate and morphine hydrochloride in the mixed micelle is 2:1. The CMC values of mixed micelles do not differ from the CMC values of the micelle constituents, which suggests that the binding of morphine hydrochloride does not perturb the hydrophobic domain of the bile acid molecule. In the presence of bile acids, the transfer rate constant (k(12)) of morphine hydrochloride from the buffered aqueous solution to chloroform (model of the cell membrane) shows a decrease. A significant decrease of the k(12) was also observed in the presence of micellar solutions. Kinetic measurements indicated that, in addition to micellar interaction between morphine hydrochloride and sodium salts of bile acids, a complex may also be formed in chloroform via hydrogen bonds formed between the drug and bile acid molecules.

The main goal of this study was to estimate the lipophilicity and investigate the molecular mechanism of retention of bile acids and their derivatives in order to find an objective manner of quantitative comparison of different chemically bonded stationary phases for high performance TLC in terms of their (dis)similarities. Highly significant correlations were obtained between different experimental indices of lipophilicity (R(M0), S and the scores corresponding to the first principal component) estimated on CN(F254s) and RP-18(F254s) and some computed log P values that combine electronic and topological aspects. The most statistically significant quantitative structure-property relationship models, using descriptors from Dragon software, multiple linear regression and genetic algorithm, were also obtained in the case of CN(F254s) and RP-18(F254s) stationary phases. Cross-validation suggests a good reliability of the results. The contribution of 2D and 3D descriptors, which are related to atomic mass, together with reactivity parameters such as polarizability and electronegativity seem to control the chromatographic mechanism (lipophilicity) on all stationary phases.