Warmed diluent speeds dantrolene reconstitution.

Abstract

To define more completely the aqueous solubility of dantrolene in order to devise faster reconstitution techniques for use during malignant hyperthermia episodes. To determine Beer's law compliance and the extinction coefficient, we measured the spectrophotometric absorbance at 385 nm of known dantrolene solutions. We added small aliquots of sterile water USP (pH 5.3; 15-40 degrees C) or buffered water (20 degrees C; pH 6.8-9.1) to dantrolene, mechanically agitated and filtered the solutions, and spectrophotometrically determined concentration. To simulate clinical reconstitution conditions, we added sterile water, 60 mL, at temperatures between 15 and 40 degrees C to dantrolene vials and measured the manual shaking time needed to create a) a suspension of small particles, and b) a clear solution. A plot of UV-vis absorbance at 385 nm vs dantrolene concentration was linear and went through the origin; the extinction coefficient is 16.1 mM(-1). At 20 degrees C, dantrolene is nearly insoluble below pH 8.8. Dantrolene is 2.8 times more soluble in 0.1 M THAM (tris-(hydroxymethyl)aminomethane) than in sterile water at pH 9.1. Dantrolene is 6.7 times more soluble in 40 degrees C than in 20 degrees C water at pH 9.5 (the pH of reconstituted dantrolene). Under clinical conditions, water temperature altered the time to create a clear solution but not a suspension (60 sec). Diluting dantrolene with 40 degrees C water rather than operating-room temperature water (20 degrees C or below) would speed dantrolene reconstitution.