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 PP  Vol.3 No.3 , July 2012
Stability Characterization, Kinetics and Mechanism of Degradation of Dantrolene in Aqueous Solution: Effect of pH and Temperature
Saeed R. Khan*, Mobin Tawakkul, Vilayat A. Sayeed, Patrick Faustino, Mansoor A. Khan
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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.
Keywords: Dantrolene; UPLC; pH; Impurity; Degradation; Compound B; C.
Cite this paper: 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.
References

[1]   T. Krause, M. U. Gerbershagen, M. Fiege and R. Wei?horn, F. Wappler, “Dantrolene—A Review of Its Pharmacology, Therapeutic Use and New Developments,” Anaesthesia, Vol. 59, No. 4, 2004, pp. 364-373. doi:10.1111/j.1365-2044.2004.03658.x

[2]   H. R. Snyder, C. S. Davis, R. K. Bickerton and R. P. Halliday, “1-[5Arylfurfurylidene)amino] Hydantoins: A New Class of Muscle Relaxants,” Journal of Medicinal Chemistry, Vol. 10, No. 5, 1967, pp. 807-810. doi:10.1021/jm00317a011

[3]   K. O. Ellis, A. W. Cas-tellion, L. J. Honkomp, F. L. Wessels, J. F. Carpenter and R. P. Halliday, “Dantrolene, a Direct Acting Skeletal Muscle Relaxant,” Journal of Pharmaceutical Science, Vol. 62, No. 6, 1973, pp. 948- 951. doi:10.1002/jps.2600620619

[4]   M. Nakano, N. Inotsume, N. Kohri and T. Arita, “Reversible Ring-Opening Reaction of Diazepam in Acid Media Around Body Temperature,” International Journal of Pharmaceutics, Vol. 3, No. 4-5, 1979, pp. 195-204. doi:10.1016/0378-5173(79)90003-6

[5]   K. A. Connors, V. J. Amidon and V. J. Stella, “Chemical Stability of Pharmaceuticals,” A Handbook for Pharmacists, John Wiley & Sons, New York, 1986.

[6]   N. Inotsume and M. Nakano, “Hydrolytic Behavior of Dantrolene in Acidic Media at Body Temperature,” International Journal of Pharmaceutics, Vol. 17, No. 2-3, 1983, pp. 357-360. doi:10.1016/0378-5173(83)90047-9

[7]   P. L. Cox, J. P. Heotis, D. Polin and G. M. Rose, “Quantitative Determination of Dantrolene Sodium and Its Metabolites by Differential pulse Polarography,” Journal of Pharmaceutical Science, Vol. 58, No. 8, 1969, pp. 987-989. doi:10.1002/jps.2600580818

[8]   J. D. Conklin and R. J. Sobers, “Qualitative Method for Dantrolene and a Related Metabolite in Urine,” Journal of Pharmaceutical Sciences, Vol. 62, No. 6, 1973, pp. 1024-1025. doi:10.1002/jps.2600620641

[9]   R. D. Hollifield and J. D. Conklin, “Determination of Dantrolene in Biological Specimens Containing Drug-Related Metabolites,” Journal of Pharmaceutical Science, Vol. 62, No. 2, 1973, pp. 271-274. doi:10.1002/jps.2600620219

[10]   M. A. Tawakkul, P. J. Faustino, V. A. Sayeed, M. A. Khan and S. R. Khan, “Development and Application of a Validated Stability-Indicating Ultra-Performance Liquid Chromatography (UPLC) Method for the Determination of Dantrolene and Its Related Impurities,” Clinical Research and Regulatory Affairs, Vol. 27, No. 1, 2010, pp. 21-29. doi:10.3109/10601331003623309

 
 
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