Stability of pibenzimol hydrochloride in commonly used infusion solutions and after filtration.

The stability of pibenzimol hydrochloride was evaluated after reconstitution, after addition to several intravenous fluids, and after filtration. Vials containing pibenzimol hydrochloride 50 mg were reconstituted with 2.5 mL of 0.9% sodium chloride injection to 20 mg/mL. For determination of drug stability in intravenous fluids, vial contents were further diluted to 0.15 mg/mL by injection into glass containers and polyvinyl chloride (PVC) bags containing 250 mL of 5% dextrose injection, 0.9% sodium chloride injection, or lactated Ringer's injection. Pibenzimol concentrations were determined immediately after preparation and at various intervals after storage at 4-6 degrees C or 25 degrees C by means of a stability-indicating, high-performance liquid chromatographic technique. Vial contents were inspected visually for color changes, and pH was measured. Determinations were also made of the stability of pibenzimol 0.15 mg/mL in 0.9% sodium chloride injection after simulated infusions using a 0.22-micron filter set at 25 degrees C. All study solutions and admixtures retained more than 90% of the initial pibenzimol concentration. The greatest loss of drug (6-7%) occurred after 24 hours in lactated Ringer's injection in both glass and PVC containers and in 0.9% sodium chloride injection in PVC bags. No drug loss occurred as a result of filtration. Reconstituted pibenzimol hydrochloride and admixtures of pibenzimol in 5% dextrose injection, 0.9% sodium chloride injection, or lactated Ringer's injection in glass or PVC containers are stable for at least 24 hours at 25 degrees C. Filtration has no effect on stability.

In vitro dynamic method for evaluating the hemolytic potential of intravenous solutions.

An in vitro dynamic method for evaluating the hemolytic potential of intravenous solutions has been developed. The method utilizes an in vitro flow system that provides a reasonable simulation of blood circulation at sites for intravenous injections. Physical variables such as internal diameter of tubing, flow rate of red blood cell (RBC) suspension and injection rate were found to significantly influence the degree of hemolysis caused by the intravenous injection of solutions. For example, injection of 50% v/v propylene glycol (PG) in 0.9% w/v aqueous sodium chloride (NaCl) solution at the rate of 5 mL/30 seconds caused 78.4 percent hemolysis when the flow rate of RBC suspension at the injection site was 12 mL/min. Increasing the flow rate of the RBC suspension at the injection site to 48 mL/min resulted in a decrease in the percent hemolysis (33.5%) caused by the above solution when injected at 5 mL/30 seconds.

Stability of terbutaline sulfate repackaged in disposable plastic syringes.

The stability of terbutaline sulfate injection repackaged in disposable plastic syringes and stored for a 60-day period under one of three conditions, dark at 4 degrees C, dark at 25 degrees C, and light at 25 degrees C, was studied. Terbutaline sulfate from 1-mg/mL ampuls was repackaged into 63 3-mL polypropylene syringes. Twenty-one syringes were protected from light by storage in ultraviolet-light-inhibiting bags in a dark cabinet. Twenty-one syringes were exposed to continuous fluorescent light at room temperature, and the remaining syringes were stored in the dark under refrigeration. Samples were visually inspected and assayed on days 0, 1, 4, 7, 14, 28, and 60 after repackaging. Drug concentrations were determined by a stability-indicating high-performance liquid chromatographic method. Terbutaline concentrations ranged from 89.2% to 98.5% of initial concentration. The contents of the light-exposed syringes had yellowed by day 60. Terbutaline sulfate in polypropylene syringes is stable for 60 days under refrigeration and at room temperature when protected from light, but substantial degradation and discoloration of the drug can occur when the syringes are not protected from light.

Pharmacokinetics of tiazofurin in dogs.

The pharmacokinetics of total and free tiazofurin, an antineoplastic agent, was studied in healthy mongrel dogs following intravenous and oral administration of the drug. The free fraction of tiazofurin was obtained from plasma by an ultrafiltration technique using a micropartition system. Total and free tiazofurin levels were determined by a sensitive high performance liquid chromatographic method. The percentage of tiazofurin bound to plasma proteins remained constant at approximately 15 per cent following administration to healthy mongrel dogs. The mean pharmacokinetic parameters of elimination rate constant (K), effective half-life (t 1/2), mean residence time (MRT) and the time to reach peak plasma level (tmax--after oral administration) were 0.32 +/- 0.04 h-1, 2.24 +/- 0.25 h, 3.23 +/- 0.36 h, and 1.78 +/- 0.50 h, respectively. The apparent volume of distribution at steady state was 0.98 +/- 0.30 1 kg-1 and the plasma clearance was 5.24 +/- 2.39 ml min-1 kg-1. About 90 per cent of tiazofurin was absorbed following oral administration. The pharmacokinetic parameters did not differ significantly between the total and free drug levels, indicating that the pharmacokinetics of total tiazofurin levels reflect those of the free tiazofurin in plasma.

Blood level studies of all-trans- and 13-cis-retinoic acids in rats using different formulations.

Studies to determine the bioavailability of all-trans-retinoic acid from a microencapsulated product were carried out using rats as test animals. The microcapsules were tableted in rat food and individual rats given a tablet containing the equivalent of 10 mg of all-trans-retinoic acid. Comparisons were made with bioavailability data obtained after intravenous and oral administrations of a solution and a suspension. The elimination of all-trans-retinoic acid following intravenous administration of 1- to 5-mg doses occurred by dose-dependent kinetics. The half-lives for the terminal linear portion of the elimination phase after the plateau level were 0.78, 0.74, and 0.93 hr for the 1-, 2.5-, and 5-mg doses, respectively. Based on the doses administered and the relative area under the serum level curves, the all-trans-retinoic acid microcapsules were found to be approximately 34% as bioavailable as the solution dosage form and the microfine suspension 93% as bioavailable. The bioavailability of all-trans-retinoic acid in oral solution was approximately 40% of the intravenous dose. For comparison, rats were also dosed intravenously with 13-cis-retinoic acid, and this compound was found not to follow dose-dependent kinetics at similar dosage levels used for all-trans-retinoic acid.

Improved and rapid high-performance liquid chromatographic assay for 13-cis-retinoic acid or all-trans-retinoic acid.

A rapid, specific, and sensitive reversed-phase high-performance liquid chromatographic (HPLC) assay for the quantitative determination of all-trans-retinoic acid (I) or 13-cis-retinoic acid (II) in rat serum without extraction of lyophilization is described. Chromatographic separation from retinol, serum components, and retinol acetate standard was achieved on octadecylsilane-coated particles with acetonitrile-1% ammonium acetate as th eluent. Serum samples (100 microliter) containing as little as 10 ng of retinoid were analyzed. Serum level profiles of rats dosed with the retinoids demonstrated the utility of the assay and indicated elimination half-lives of 0.58 and 0.92 hr for I and II, respectively.

Effect of macromolecules on aqueous solubility of cholesterol and hormone drugs.

The solubility of cholesterol and some hormone drugs in aqueous macromolecule solutions was investigated. Polyvinylpyrrolidone, dextrans, and heparin increased the solubilities of progesterone, testosterone, and diethylstilbestrol, while acacia, pectin, and carrageenans decreased their solubilities. Dextrans increased the solubilities of cholesterol and the three hormone drugs. Acacia and pectin greatly increased cholesterol solubility; however, these macromolecules significantly decreased progesterone and diethylstilbestrol solubilities and slightly decreased progesterone solubility. Heparin decreased cholesterol solubility and increased progesterone, testosterone, and diethylstilbestrol solubilities. Carrageenans significantly decreased cholesterol, progesterone, and testosterones solubilities and had little effect on diethylstilbestrol solubility. A strong bathochromic shift in the absorption spectra of progesterone and testosterone in polyvinylpyrrolidone solutions indicated an attachment between the polymer and the C=O group of the steroids.

Automated potentiometric procedure for studying dissolution kinetics acidic drugs under sink conditions.

An automated potentiometric procedure was used for studying in vitro dissolution kinetics of acidic drugs. Theoretical considerations indicated that the pH-stat method could be used to establish approximate sink conditions or, possibly, a perfect sink. Data obtained from dissolution studies using the pH-stat method were compared with data obtained from known sink and nonsink conditions. These comparisons indicated that the pH-stat method can be used to establish a sink condition for dissolution studies. The effective diffusion layer thicknesses for benzoic and salicylic acids dissolving in water were determined, and a theoretical dissolution rate was calculated utilizing these values. The close agreement between the experimental dissolution rates obtained under pH-stat conditions and theoretical dissolution rates indicated that perfect sink conditions were established under the experimental conditions used.

Nitrofurantoin solubility in aqueous urea and creatinine solutions.

Experiments were carried out to determine the effect of urea and creatinine on the solubility of nitrofurantoin in water at different temperature and pH conditions. The addition of urea to aqueous media increased nitrofurantoin solubility up to a maximum concentration level and then decreased solubility at higher urea concentrations. The amount of urea needed to bring about maximum nitrofurantoin solubility was dependent on temperature and ranged between 1.75 and 2.50%. Spectral studies suggest a possible interaction between urea and nitrofurantoin molecules. Nitrofurantoin solubility increased with an increasing creatinine concentration ranging from 0.05 to 1.6%. Spectral studies indicate a strong interaction between creatinine and nitrofurantoin molecules in solution. The combined effect of urea and creatinine of the solubility of nitrofurantoin could account for the absence of crystalluria with this drug, even though unusually high concentrations in urine have been reported.

Effects of various hydrodynamic conditions on dissolution rate determinations.

An automated potentiometric procedure was used in dissolution rate studies to determine the effects of various hydrodynamic conditions on dissolution rate determinations. Changes in the hydrodynamics of the system resulted from using various sizes and shapes of dissolution vessels. Dissolution rate constants for benzoic acid prills in distilled water at pH-stat 6.2 were used as a measure of the agitation intensities present in the different shaped vessels. Great variations in the dissolution rates occurred in vessels with the same diameter and stirrer blade position when the shapes of the bottom of the vessel were varied. A similar order of dissolution rates was obtained at 100 and 150 rpm for the individual vessels at various propeller heights. The order differed from one vessel to another, depending on the shape of the bottom (concave, convex, or flat) of the vessel. In some cases, a change in the type of bottom resulted in the opposite order of rates for vessels with the same diameter.

Behavior of erythrocytes in ternary solvent systems.

The effect of ternary solvent systems on erythrocytes was investigated. Hemolysis experiments were run at 37degree in solutions containing various amounts of water, two nonaqueous solvents, and 0.9% sodium chloride. The nonaqueous solvents were propylene glycol, polyethylene glycol 400, dimethyl sulfoxide, dimethylformamide, and tetramethylurea. Ternary diagrams based on the critical hemolytic compositions of the various ternary systems are presented.