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Abstract
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.
Highlights
Dantrolene is widely used as a muscle relaxant and for the treatment of malignant hyperthermia [1,2]
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
The degradation of dantrolene in buffers over pH 1.2 - 9.5 at 35 ̊C resulted in appearance of two degradation product compounds B and C with a retention time equivalent to 1.1 min and 2.1 min in the ultra-performance liquid chromatographic (UPLC) chromatogram (Figure 3)
Summary
Dantrolene is widely used as a muscle relaxant and for the treatment of malignant hyperthermia [1,2]. Despite the importance of this drug as a powerful muscle relaxant, little is known about the temperature and pH dependence on dantrolene’s degradation in aqueous solution. Dantrolene was reported to undergo hydrolysis in alkaline solution causing it to degrade via hydantoin ring opening to form an open ring compound (designated as compound B) (Figure 1) but no report has been published on a possible catalytic hydrolysis of dantrolene in neutral or acidic media at different temperatures [3]. Dantrolene is in part structurally related to nitrofurantoin and furatadone and contain an azomethime bond (-N=CH-) [4]. The degradation of drugs containing azomethine bond in
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