Influence of formulation properties on chemical stability of captopril in aqueous preparations.

The influence of various formulation properties on the chemical stability of captopril in aqueous media at pH 3 was investigated, in order to reformulate and increase the shelf-life of an oral mixture of the drug. At this pH, chemical stability is improved by an increase in drug concentration (1-5 mg/ml) and a decrease in temperature (5-36 degrees C), the latter demonstrated by a linear Arrhenius-plot. The activation energy is low (Ea = 10.2 kcal/mol), thus the Q10 value is only 1.8 in pure aqueous solutions. The degradation at the lowest concentration investigated in pure aqueous solution apparently follows zero order kinetics. The reaction order is changed at higher concentrations. We are presenting a hypothesis of intramolecular proton transfer from the thiol to the ionized carboxylic group as the initial step in the oxidative degradation pathways of captopril. Long-term stability of 1 mg/ml captopril in aqueous solutions at pH 3, stored at 36 degrees C for one year, shows that the sugar alcohol sorbitol accelerates degradation of the drug while Na-EDTA at a concentration as low as 0.01% is sufficient to stabilize these samples. Purging with N2-gas prior to storage is not essential for drug stability, as long as Na-EDTA is present. Only at a low level of Na-EDTA (0.01%) combined with a high level of sorbitol (35%), purging with N2-gas appears to have a small effect. The destabilizing effect of sugar alcohols is confirmed by accelerated degradation also in the presence of glycerol. The efficient stabilization in the presence of Na-EDTA at a low concentration indicates that the metal-ion-catalyzed oxidation pathway dominates the chemical degradation process at low pH, although several mechanisms seem to be involved depending on excipients present.

Stability of dopamine hydrochloride 0.5 mg/mL in polypropylene syringes.

OBJECTIVE: To determine the stability of dopamine hydrochloride diluted to 0.5 mg/mL in isotonic glucose infusion and stored in 50 mL polypropylene syringes from two different suppliers. METHODS: Polypropylene syringes containing dopamine hydrochloride 0.5 mg/mL were stored protected from light at 25 degrees C/60% relative humidity for 1 week, at 4 degrees C/ambient humidity for 3 months and at -20 degrees C/ambient humidity for 6 months. Samples were periodically withdrawn and the concentration of dopamine hydrochloride determined using a stability-indicating high-performance liquid chromatography method. The appearance of the solutions with respect to colour, clarity and precipitation was studied and the pH of the solutions measured. RESULTS: The concentration of dopamine hydrochloride in the solutions remained at least 95% of the initial concentration after storage at 25 degrees C for 1 week and at 4 degrees C for 3 months. Variation in dopamine concentration was observed in syringe samples, stored frozen, from two suppliers. The mean concentration was >/=95% for product stored in syringes from Codan and >/=90% of initial concentration when stored in syringes from Braun. In some of the syringes from Braun, the concentration was lower than 90%. The samples in all syringes had to be homogenized after thawing to give a uniform solution. There were no other evident changes in the physical appearance or pH of the solutions during the study. CONCLUSION: Dopamine hydrochloride 0.5 mg/mL in isotonic glucose solution is stable when protected from light for 1 week at 25 degrees C/60% relative humidity and for 3 months at 4 degrees C/ambient humidity in Codan and Braun syringes. The cause of content variability observed in solutions stored frozen in Braun syringes needs further investigation. Braun syringes should not be used if the product is to be frozen. The stability of the frozen product, in Codan syringes is 6 months.

Air-filled polymeric microcapsules from emulsions containing different organic phases.

Air-filled polymeric microcapsules for use as a contrast agent in ultrasonography have been prepared by the freeze-drying of different oil-in-water emulsions. The water phases consisted of a block copolymer in water. The organic phases consisted of a biodegradable polyester dissolved in (-)-camphene, cyclooctane, cyclohexane or tricyclene, which were relatively poor solvents for the polyester. A polymeric wall was, therefore, precipitated at the droplet surface early in the process, i.e. during freezing. Removing the solvent during freeze-drying, resulted in air-filled microcapsules. The microcapsules were suspended in saline after freeze-drying. All the suspensions contained echogenic microcapsules with a volume mean diameter of approximately 5-7 microm. Microscopic investigations showed that the microcapsules were spherical and hollow. Tricyclene and, to some degree, (-)-camphene were found unsuitable for industrial production due to melting points above 30 degrees C. Cyclooctane and cyclohexane were investigated as replacements for the initially chosen (-)-camphene, since they are liquids over a wider temperature range. These solvents gave improved yields, measured both as particle volume concentration per amount of polymer in suspension and acoustic attenuation at 3.5 MHz per amount of polymer in suspension, although the freeze-drying cycle was not optimized for these systems.