Barbara L. Hoesterey

Solubilization of Thiazolobenzimidazole Using a Combination of pH Adjustment and Complexation with 2-Hydroxypropyl-β-Cyclodextrin

The thiazolobenzimidazole l-(2,6-difluorophenyl)-lH,3H-thiazolo[3,4-a]benzimidazole, TBI, is an experimental drug for the treatment of AIDS which exhibits a low water solubility (11 µg/mL) and is therefore difficult to administer in an injectable solution dosage form at a target solution concentration of 10 mg/mL. The compound has a single ionizable functional group and exhibits an increase in solubility with decreasing pH consistent with a pKa of 3.55, but the maximum solubility attainable by pH adjustment has been shown to be only 0.4 mg/mL (at pH 2). TBI has been found to form inclusion complexes in either its neutral or its protonated form with 2-hydroxypropyl-β-cyclodextrin (HPCD). The equilibrium constants for 1:1 complex formation were found to be 81 and 1033 M−l for the protonated and neutral species, respectively. Although the formation of protonated complex is less favored in comparison to the neutral complex, the contribution of this species to the overall solubility of TBI predominates at low pH. Thus, using a combined approach of pH adjustment and complexation with HPCD, a solubility enhancement of 3 orders of magnitude is possible. NMR proton spectroscopy and molecular modeling studies, conducted to understand the orientation of TBI in the complex and the effect of protonation, are described.

Brain and cerebrospinal fluid uptake of zidovudine (AZT) in rats after intravenous injection

Uptake kinetics of zidovudine into cerebrospinal fluid (CSF) and brain tissue were determined in adult Sprague Dawley male rats after single intravenous injection of 6.7 mg/kg (25 mumol/kg). The drug kinetics in plasma followed biexponential disposition with an initial distribution half-life of approximately 11 minutes and an elimination half-life of 40 minutes. Over the plasma concentration range of 0.2 to 10 micrograms/ml, the cerebrospinal fluid to plasma ratio averaged 14.8 +/- 1.9% whereas the mean brain tissue to plasma ratio was 8.2 +/- 1.2% (uncorrected) or 2.3 +/- 1.8% (corrected) for the brain vascular space contribution. Simultaneous nonlinear regression analysis of brain, CSF and plasma concentration data indicate that the overall rate constant for efflux of drug from brain is approximately 75-fold higher and from CSF is 8-fold higher than the respective rate constants for influx. Thus, the ratio of the efflux to influx appears to be the predominant factor in determining the net accumulation of drug into CSF and brain parenchymal tissue.

The triplet state IR spectrum of matrix-isolated anthracene

Abstract The lowest triplet state infrared spectrum of matrix-isolated anthracene between 1650 and 550 cm−1 is reported. The seven triplet state bands were tentatively assigned based on frequency proximity to ground state absorptions and comparisons with triplet state features in similar molecules.

Effects of low temperature air oxidation (weathering) reactions on the pyrolysis mass spectra of US coals

Abstract Two high volatile bituminous coals (Upper Freeport and Hiawatha seams), a subbituminous coal (Adaville seam) and a lignite (Anderson seam) were used to investigate the effect of low temperature air oxidation (‘weathering’) on the yield and composition of vacuum pyrolysis products. Fresh coal samples were exposed to air at 80 and 100°C for up to 10 days under controlled laboratory conditions. Curie-point pyrolysis mass spectrometry combined with computerized data analysis was applied to study the weathering induced changes in a series of samples weathered for various lengths of time. It was found that the abundance of small oxygen-containing molecules such as carbon monoxide, carbon dioxide and aliphatic carboxylic acids increased in the pyrolysate of all samples, whereas phenols and dihydroxybenzenes showed decreased yields, especially in the two lowest rank coals. Besides phenols, alkylnaphthalenes and alkyltetralins showed decreased abundances in the pyrolysis mass spectra of the two high volatile bituminous coals. An attempt is made to explain the difference in pyrolysis patterns observed before and after weathering experiments in terms of underlying structural changes.