Dantrolene sodium solubility and stability in excipients for emergency parenteral malignant hyperthermia treatment

To investigate whether a clinically relevant solution of dantrolene sodium (DS) (defined as ≥1 mg mL^-1) could be produced using available, safe-to-use solvents for emergency preparation and parenteral administration in veterinary species.

Laboratory study.

DS used in the investigation was from both commercially available oral capsules (DS-cap) and chemical-grade DS (99.9% pure). The DS was dissolved in various solvents using a 25-minute abbreviated shake-flask method and sonication. Ultraviolet absorbance at 387 nm was recorded and concentrations were extrapolated from a dimethylformamide calibration curve. Solvents were titrated to pH 9.5-10 using aliquots of 0.4% sodium hydroxide to assess the influence of pH on DS solubility. Descriptive statistical analyses were performed on resultant data.

Initial solvent screening identified that 0.9% sodium chloride, 7.2% hypertonic saline, lactated Ringer's solution, and 50% polyethylene glycol 400 failed to reach predefined target concentrations. Other solvents, including 5% dextrose (D5W) and 20% ethanol (EtOH), failed to reach concentrations ≥ 1 mg mL^-1, but stability was maintained over 24 hours. Titrating the solvent pH to 9.5-10 enhanced DS solubility and stability in all tested solvents. Titrated solutions containing 20% N-methyl-2-pyrrolidone and 50% polyethylene glycol 300, with 20% EtOH and D5W as cosolvents, produced DS concentrations of at least 5 mg mL^-1 for both DS-cap and chemically pure (99.9%) DS.

Multiple solvents and solvent systems investigated demonstrated possibilities for a clinically relevant formulation of DS. DS may be suitable for compounding for off-label use if a patient is known to be malignant hyperthermia (MH) positive or following early MH detection. The safety profile, pharmacokinetic and pharmacodynamic data are still needed.