RESUMO

In drug design experimental characterization of acidic groups in candidate molecules is one of the more important steps prior to the in-vivo studies. Potentiometry combined with Yasuda-Shedlovsky extrapolation is one of the more important strategy to study drug candidates with low solubility in water, although, it requires a large number of sequences to determine pKa values at different solvent-mixture compositions to, finally, obtain the pKa in water (pwwKa) by extrapolation. We have recently proposed a method which requires only two sequences of additions to study the effect of organic solvent content in liquid chromatography mobile phases on the acidity of the buffer compounds usually dissolved in it along wide ranges of compositions. In this work we propose to apply this method to study thermodynamic pwwKa of drug candidates with low solubilities in pure water. Using methanol/water solvent mixtures we study six pharmaceutical drugs at 25 °C. Four of them: ibuprofen, salicylic acid, atenolol and labetalol, were chosen as members of carboxylic, amine and phenol families, respectively. Since these compounds have known pwwKa values, they were used to validate the procedure, the accuracy of Yasuda-Shedlovsky and other empirical models to fit the behaviors, and to obtain pwwKa by extrapolation. Finally, the method is applied to determine unknown thermodynamic pwwKa values of two pharmaceutical drugs: atorvastatin calcium and the two dissociation constants of ethambutol. The procedure proved to be simple, very fast and accurate in all of the studied cases.

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RESUMO

We measured pKa values of Tris(hydroxymethyl)aminomethane and dihydrogen phosphate; both are commonly used to prepare buffers for reverse-phase liquid chromatography (RPLC), in acetonitrile/water mixtures from 0% to 70% (v/v) (64.6% (w/w)) acetonitrile and at 20, 30, 40, 50, and 60°C. The procedure is based on potentiometric measurements of pH of buffer solutions of variable solvent compositions using a glass electrode and a novel automated system. The method consists in the controlled additions of small volumes of a thermostated solution from an automatic buret into another isothermal solution containing exactly the same buffer-component concentrations, but a different solvent composition. The continuous changes in the solvent composition induce changes in the potentials. Thus, only two sequences of additions are needed: increasing the amount of acetonitrile from pure water and decreasing the content of acetonitrile from 70% (v/v) (64.6% (w/w)). In the procedure with homemade apparatus, times for additions, stirring, homogenization, and data acquisition are entirely controlled by software programmed for this specific routine. This rapid, fully automated method was applied to acquire more than 40 potential data covering the whole composition range (at each temperature) in about two hours and allowed a systematic study of the effect of temperature and acetonitrile composition on acid-base equilibria of two widely used substances to control pH close to 7. The experimental pKa results were fitted to empirical functions between pKa and temperature and acetonitrile composition. These equations allowed predictions of pKa to estimate the pH of mixtures at any composition and temperature, which would be very useful, for instance, during chromatographic method development.

RESUMO

Distribution coefficients K of n-alkanes were determined in wide ranges of temperature and carbon numbers from gas chromatographic retention data measured on wall-coated poly(dimethylsiloxane) commercial capillary columns. A discussion is centered on how to mitigate the difficulties for an accurate determination of K when using weakly retentive columns, as those bearing very high phase ratios or short lengths. Particularly, the errors associated with the estimation of the gas hold-up and the phase ratio of the column are considered. The chromatographic importance for determining K of n-alkanes relies on the fact that these are the most commonly applied references for reporting relative thermodynamic parameters such as the Kovats Index and the relative retention. A great amount of information has been compiled in this form. If K of the reference is known, absolute values of distribution coefficients for a myriad of substances are readily obtainable. The knowledge of K(T) functions of solutes in wide ranges of temperature is a primary necessity in temperature-programmed gas chromatography. This knowledge is needed for the prediction of absolute retention times and for computing separation optimizations of mixtures containing several critical pairs of analytes.

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RESUMO

Sixty-four neonates, with gestational age ranging from 27 1/2 to 40 weeks, postnatal age from 1 to 15 days, and birth weight from 800 to 3400 gm, were given netilmicin 2.5 mg/kg intramuscularly two or three times per day according to postnatal age, for 5 to 14 days. Serum concentrations were measured before and 1 hour after a dose at least twice during treatment. The serum washout profile of the drug was observed in 22 neonates after discontinuation of therapy. Renal function was studied in 37 infants by measuring serum creatinine concentrations and in 27 by urinary excretion of N-acetyl-glucosaminidase during and up to 15 days after therapy. Behavioral and impedance audiometry, and in infants failing those, auditory brainstem evoked response tests, were performed between 6 and 12 months of age. In 23.5% of the neonates, trough serum levels were greater than 3 micrograms/ml. The serum washout followed a multiexponential decay, accounting for distributional, rapid (initial), and slow (tissue) elimination phases. Linear regression analysis performed between each kinetic parameter and gestational age or birth weight showed that initial elimination half-life, steady-state volume of distribution, and total body clearance were significantly correlated with both variables. Netilmicin did not cause detectable renal or auditory damage.

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