Stability of cefonicid sodium in infusion fluids.

The chemical stability of cefonicid sodium in infusion fluids was analyzed. Cefonicid sodium vials were reconstituted and diluted with sterile water for injection and other commonly used intravenous fluids to concentrations of 325, 220, 40, 20, and 5 mg/mL. Cefonicid concentration was analyzed by high-performance liquid chromatography initially and after storage at room temperature and 5 degrees C. Reconstituted vials were frozen as long as eight weeks, thawed, and kept at room temperature and 5 degrees C and then analyzed. Cefonicid sodium reconstituted in each of the diluents studied exhibited no change in clarity and very little change in potency after 24 hours at room temperature and after 72 hours at 5 degrees C. Some vials with high concentrations became turbid between 72 and 96 hours at 5 degrees C. The thawed vials were chemically stable for 24 hours at room temperature and for 96 hours at 5 degrees C. When reconstituted with sterile water for injection and other commonly used intravenous fluids, cefonicid sodium vials and small-volume infusions are chemically stable for 24 hours at room temperature and for 72 hours at 5 degrees C. Reconstituted cefonicid sodium vials can be frozen and stored for as long as eight weeks, thawed, and then kept at room temperature for 24 hours or at 5 degrees C for 72 hours.

A dissolution anomaly involving ticrynafen in simulated intestinal fluid without enzyme.

Data are presented showing that the anomalous dissolution behavior of ticrynafen in simulated intestinal fluid without enzyme is due to the presence of potassium ions in the dissolution medium. Solubility studies indicate that an insoluble 1:1 complex is formed between ticrynafen and its potassium salt. This complex apparently creates an insoluble barrier that prevents complete dissolution of ticrynafen. To determine whether this might also occur in clinical use, a three-way cross-over study in 12 subjects was done. Data from this investigation show that concomitant administration of ticrynafen tablets and potassium in the form of a commercial supplement does not adversely affect bioavailability.

Degradation kinetics of a new cephalosporin derivative in aqueous solution.

The degradation kinetics of a new cephalosporin derivative (1) in aqueous solution were investigated at 60 degrees, mu = 0.05, at pH 2.0-10.0. The observed degradation rates followed pseudo-first-order kinetics and were influenced significantly by H2O and OH- catalysis. No primary salt effect was observed in the acid region, but a positive salt effect was observed at pH 9.4. A general base catalytic effect by a phosphate buffer species was observed at pH 7-8. The pH-rate profile for I exhibited a degradation minimum at pH 6.05. The Arrhenius activation energies determined at pH 4.0 and 9.4 were 27.2 and 24.5 kcal/mole, respectively. Excellent agreement between the theoretical pH-rate profile and the experimental data supported the hypothesized degradation process. A comparison of I and cefazolin revealed close structural and stability analogies.

Degradative behavior of a new bronchodilator, carbuterol, in aqueous solution.

The degradation kinetics of carbuterol in aqueous solution were investigated at 85 degrees and constant ionic strength over the pH 0.25--13.3 range under anaerobic conditions. The results demonstrated a complex kinetic pattern involving specific acid and specific base catalyses at the pH extremes. Degradation resulted primarily from intramolecular catalysis and indicated that both the protonated and unprotonated phenolic groups participated in the reaction. High-pressure liquid chromatography was used to isolate carbuterol and its degradation product. Mass spectrometric examination showed that the degradation product was a cyclized derivative formed by intramolecular attack of the phenoxy group on the ureido carbonyl with ammonia expulsion. The apparent activation energy for carbuterol at pH 4.0 and 10.0 was 22.3 and 11.7 kcal/mole, respectively. The agreement between the calculated theoretical pH--rate profile and the experimental points supports the hypothesis presented concerning the reactions involved in carbuterol degradation.

Kinetics of degradation of cefazolin and cephalexin in aqueous solution.

The kinetics of degradation of cefazolin and cephalexin in aqueous solution were investigated at 60 degrees C and constant ionic strength over the entire pH range. The observed degradation rates were obtained by measuring the residual cephalosporin and were shown to follow pseudo-first-order-kinetics. They were influenced significantly by solvolytic and hydroxide ion catalysis. No primary salt effect was observed in the acid or basic pH region. Of the buffer systems employed in the kinetics studies only the phosphate buffer system showed a catalytic effect. The pH-rate profile for cefazolin showed a degradation minimum between pH 5.5 and 6.5. Cephalexin did not show a pH minimum in that region. The apparent energies of activation were determined for cefazolin and cephalexin at pH 5.5 and were calculated to be 24.3 Kcal/mole and 26.2 Kcal/mole, respectively. The agreement between the calculated theoretical pH-rate profiles and the experimental points for both compounds support the hypothesis presented concerning the reactions involved in their respective degradation pathways.

Micelle formation and its relationship to solubility behavior of 2-butyl-3-benzofuranyl-4-(2-(diethylamino)ethoxy)-3,5-diiodophenyl ketone hydrochloride.

Micelle formation by 2-butyl-3-benzofuranyl-4-[2-(diethylamino)ethoxy]-3,5-diiodophenyl ketone hydrochloride was studied by conductance measurements. The CMC was approximately 0.05% and was independent of temperature between 20 and 50degree. The heat of formation for the micelle was calculated to be 6.9 kcal/mole. The unusual solubility behavior of the compound was attributed to its ability to form micelles. Ultracentrifuge studies indicate the molecular weight of the micelle to be approximately 100,000. Anions such as chloride, sulfate, acetate, tartrate, and citrate significantly affect the equilibrium solubility of the compound. NMR spectroscopic data indicate that the solubility behavior, in part, is related to an effect on the CMC of the compound by the anionic environment.

Pharmacokinetic interpretation of blood levels and urinary excretion data for cefazolin and cephalothin after intravenous and intramuscular administration in humans.

Blood levels of cefazolin and cephalothin were determined in two separate crossover studies in 20 healthy male adults, each after intravenous and intramuscular administration. Pharmacokinetic parameters were calculated from the intravenous data based upon a two-compartment open model. The rate constants controlling the distribution between the central and peripheral compartments, the overall elimination rate constants, the apparent volumes of distribution, and the fraction of the dose in the central and peripheral compartments were determined. The bioavailability was calculated to be 100% for cefazolin and cephalothin.

Cholesterol solubility in lecithin-bile salt systems.

The method of sample preparation can markedly influence the rate of dissolution and attainment of supersaturated states of cholesterol. The equilibrium solubility of cholesterol, studied as a function of its physical state in a model bile system, is almost half that of previously accepted values. Slow attainment of the equilibrium state may have acted to bias previous studies. Extrapolation of our data to the clinical situation reveals that many persons considered normal by present standards actually possess bile that is supersaturated with respect to cholesterol and are thus potential gallstone formers.