Author(s)

Saeed R. Khan, Mobin Tawakkul, Vilayat A. Sayeed, Patrick Faustino, Mansoor A. Khan

Division of Product Quality Research, Office of Pharmaceutical Science, Food and Drug Administration, Life Science Building 64, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA;.
Office of Generic Drugs, Food and Drug Administration, 7500 Standish Place, Rockville, MD 20855, USA..

The mechanism of degradation of dantrolene in aqueous buffer solutions was studied at various pH values in the range of pH 1.2-9.5 and at temperatures ranging from 25℃ to 75℃ to determine the optimum pH and temperature requirements for its stability and eventual product performance over the human gastrointestinal pH range. Dantrolene was analyzed by reversed phase ultra-performance liquid chromatographic (UPLC). Chromatographic separation was achieved on a Waters Acquity UPLC system using a Waters BEH C18 analytical column and Waters BEH C18 guard column. The compounds were eluted with a linear acetonitrile gradient (25%-75%) over three minutes with a buffer composition of 2.0 mM of sodium acetate at pH 4.5 for degradation studies. The flow rate was maintained at 0.5 mL/min. Column temperature was maintained at 35℃. Injection volume was 4 μL and the degradation products were detected by a photodiode array (PDA) detector at 375 nm. Degradation products, including compound B and C were analyzed by mass spectroscopy (MS) and nuclear magnetic resonance spectroscopy (NMR) and the degradation pathways were proposed. Degradation of dantrolene followed pseudo first–order kinetics and a V-shaped pH-rate profile over the pH range 1.2-9.5. The maximum stability was observed at pH 7.4 and 37℃. Although the focus of this paper was on the mechanism of hydrolysis of dantrolene, the poor aqueous solubility of dantrolene, the developed understanding can be utilized to improve the quality of the formulation and the risk associated with the extravasation of dantrolene sodium solution in its current form.

Dantrolene; UPLC; pH; Impurity; Degradation; Compound B; C.

S. R. Khan, M. Tawakkul, V. A. Sayeed, P. Faustino and M. A. Khan, "Stability Characterization, Kinetics and Mechanism of Degradation of Dantrolene in Aqueous Solution: Effect of pH and Temperature," Pharmacology & Pharmacy, Vol. 3 No. 3, 2012, pp. 281-290. doi: 10.4236/pp.2012.33037.