Long-term stability of ready-to-use 1-mg/mL midazolam solution

Abstract

Purpose: Midazolam is a benzodiazepine derivative commonly used in intensive care units to control sedation. Its use requires dilution of a 5-mg/mL commercial solution to a target concentration of 1 mg/mL. A study was conducted to evaluate the stability of diluted ready-to-use 1-mg/mL midazolam solutions over 365 days when stored in cyclic olefin copolymer vials or polypropylene syringes.

Methods: A specific stability-indicating high-performance liquid chromatography coupled with UV detection method was developed for midazolam hydrochloride and validated for selectivity, linearity, sensitivity, precision, and accuracy. Three storage conditions were tested: -20°C ± 5°C, 5°C ± 3°C, and 25°C ± 2°C at 60% ± 5% relative humidity. Half of the vials were stored upside down to test for the absence of interaction between midazolam and the stopper. Particle contamination, sterility, and pH were assessed.

Results: The limit of stability was set at 90% of the initial concentration. After 1 year's storage at -20°C and 5°C, concentrations remained superior to 90% under all storage conditions. At 25°C, stability was maintained up to day 90 in syringes (mean [SD], 92.71% [1.43%]) and to day 180 in upright and upside-down vials (92.12% [0.15%] and 91.57% [0.15%], respectively). No degradation products were apparent, no variations in pH values were detected, and containers retained their sterility and conformity with regard to any specific contamination during the study.

Conclusion: The evaluated 1-mg/mL midazolam solution was stable over a 1-year period when stored at a refrigerated (5°C) or frozen (-20°C) temperature in both vials and syringes; with storage at 25°C, the stability duration was lower. The preparation of ready-to-use midazolam solutions by a hospital pharmacy is compatible with clinical practice and could help to decrease risks inherent in dilution in care units.

Keywords: infusion; liquid chromatography; midazolam; stability-indicating method.