Stability of esmolol hydrochloride in intravenous solutions.

The stability of esmolol hydrochloride in a variety of i.v. solutions was studied. Solutions of esmolol hydrochloride 10 mg/mL were prepared separately in 0.45% sodium chloride injection, 0.9% sodium chloride injection, 5% dextrose injection, 5% dextrose and 0.45% sodium chloride injection, 5% dextrose and 0.9% sodium chloride injection, 5% dextrose with lactated Ringer's injection, lactated Ringer's injection, 5% sodium bicarbonate injection, and 5% dextrose injection with potassium chloride 40 meq/L. One glass and one polyvinyl chloride container of each solution (except glass only in the case of the solution in 5% sodium bicarbonate injection) were stored in the dark at 5 degrees C, under ambient room light at 23-27 degrees C, in the dark at 40 degrees C, and under intense light at 25-30 degrees C. At storage intervals up to 168 hours, samples were tested for esmolol hydrochloride concentration by high-performance liquid chromatography. Optical density and pH were also measured. Esmolol hydrochloride was stable in the various i.v. fluids for at least 168 hours when stored at 5 degrees C or 23-27 degrees C, for at least 24 hours when stored under intense light, and, with one exception, for at least 48 hours when stored at 40 degrees C. When mixed with 5% sodium bicarbonate injection, the drug was stable for only about 24 hours at 40 degrees C. There were no substantial changes in optical density or pH. The type of container had no effect on stability. With one exception, esmolol hydrochloride was stable in all the i.v. solutions under all the conditions tested.

An accurate prediction of the pH change due to degradation: correction for a "produced" secondary buffering system.

Esmolol hydrochloride degrades in aqueous solutions by the hydrolysis of a labile aliphatic carboxyester group. The products are methanol and ASL-8123. The resulting aliphatic carboxylic acid moiety (ASL-8123) has a pK of 4.80, which is within 1 pH unit of the pH of the formulation. ASL-8123 therefore acts as a "secondary buffer" and minimizes the change in pH due to degradation. Equations are presented to calculate the change in the pH when the primary degradation product acts as a secondary buffer. This information can be used in the development of a parenteral product to predict, a priori, the concentration of buffer necessary for optimal pH maintenance. This knowledge can reduce the number of formulation screens required to determine the necessary buffer capacity for optimal drug stability.

Stability of nitroglycerin solutions in polyolefin and glass containers.

The stability of nitroglycerin in concentrations of 200 and 400 micrograms/ml in eight common intravenous solutions was studied. Two containers of each solution at each concentration, one glass and one polyolefin, were stored under each of the following conditions: intense light (1400-2000 foot-candles) and ambient room temperature (18-27 degrees C), normal light and ambient room temperature, dark and 40 degrees C, and dark and 5 degrees C. All samples were tested at 0 and 24 hours. Room temperature and refrigerated samples were also tested at 48 hours, 7 days, and 1 month. Testing included measurement for optical density at 400 and 600 nm, pH, and nitroglycerin content as determined by HPLC. The admixtures remained clear and colorless, and no appreciable changes in pH were observed. HPLC assays showed no significant changes in nitroglycerin concentrations. There were no differences in the stability of the admixtures stored in the glass and polyolefin containers. Nitroglycerin is compatible with each of the common intravenous solutions tested under the storage conditions and in the containers used for this study.

Bretylium tosylate intravenous admixture compatibility. I: Stability in common large-volume parenteral solutions.

The stability of bretylium tosylate in 11 common large-volume parenteral solutions was studied. Two containers of each solution, one glass and one plastic (except for mannitol and sodium bicarbonate solutions, which were available in glass only), were stored at each of the following conditions: intense light (1400-2000 foot candles), ambient room temperature with normal light, 40 degrees C, and 4 degrees C. All samples were tested at 0 and 24 hours; some samples were also tested at 48 hours and 7 days. Testing included measurement for optical density at 4000 and 600 nm, pH level, and bretylium content as determined by HPLC. The admixtures remained clear and colorless, except that mannitol precipitated out of mannitol solutions stored at 4 degrees C. No appreciable changes in pH were observed. HPLC assays showed no significant changes in bretylium tosylate concentrations. Bretylium tosylate is compatible with each of the 11 common intravenous solutions chosen for investigation under the storage conditions studied. Admixtures with mannitol should not be refrigerated, because mannitol crystallizes from solution at refrigerator temperatures.

Nitroglycerin compatibility with intravenous fluid filters, containers, and administration sets.

The effect of intravenous filters, containers and administration sets on nitroglycerin potency was studied. Solutions of nitroglycerin (50 and 100 microgram/ml) in water for injection, in 5% dextrose injection and in 0.9% sodium chloride injection were prepared. The concentration of these solutions was measured after (1) filtration through a 0.2-micron filter, (2) storage in glass and plastic containers and (3) administration through eight i.v. administration sets. Filters decreased nitroglycerin concentration by 2--55%. Nitroglycerin concentration was not changed after storage for 48 hours in glass bottles. In plastic i.v. bags, concentration decreases were substantial and related to surface contact area and storage temperature. The i.v. administration sets caused immediate, substantial decreases in nitroglycerin concentration that were a function of drip rate, surface area, length of exposure to tubing, and tubing materials. The study suggests that concentrations of nitroglycerin solutions could be reduced by as much as 80% when filtered, placed in a plastic i.v. bag and given through an i.v. administration set.