Multinuclear NMR (1H, 13C and 19F) spectroscopic re-examination of the solvolytic behaviour of flurazepam dihydrochloride.
The dissolution of reference and archival samples of flurazepam dihydrochloride (2) was studied in DMSO-d6 and in D2O by 1H-, 13C- and 19F-NMR spectroscopy to identify and distinguish solvated species of the parent drug (2), the "benzophenone" (4) and glycine (5) hydrochloride degradation products. In DMSO-d6, for most samples, only the ring intact form (2) could be detected by 13C-NMR whereas the inherently greater sensitivity of 19F-NMR allowed detection of initial trace amounts (< 1%) of the open-ring form (3). 19F-NMR spectroscopy also afforded the best means of quantifying the various entities in solution, including the increase towards equilibrium levels of the open-ring entity and detection/quantitation of a new equilibrium species, possibly the cis/trans rotamer of the open-chain entity (3). Various chemical shifts for flurazepam dihydrochloride and USP flurazepam related reference standards C and F are reported for DMSO-d6 solutions. The bases for 1H- and 19F-NMR assay of DMSO-d6 solutions of (2) for (4) are discussed with comparative data. The solvation characteristics of (2) in D2O at 0 and 27 degrees C were found to be too complex to follow by 13C-NMR; however, 19F-NMR studies at these temperatures permitted one to clearly discern that no additional formation of entity (4) occurred beyond whatever initial levels were present in degraded samples while the open-ring entity (3) was observed to increase to an equilibrium level of 56% over 24 h at 27 degrees C. Dissolution in D2O at either 0 or 27 degrees C does not contribute to solvolytic degradation of (2) to (4) over 24 h.
Health Protection Branch, Health Canada, Ottawa, Ontario.
B A
BA
Dawson
D B
DB
Black
G A
GA
Neville
D002247:Carbon Isotopes; D004121:Dimethyl Sulfoxide; D004355:Drug Stability; D005462:Fluorine Radioisotopes; D005479:Flurazepam / Q000032:analysis*; D006859:Hydrogen / Q000032:analysis; D009682:Magnetic Resonance Spectroscopy; D012997:Solvents
D002247:Carbon Isotopes; D005462:Fluorine Radioisotopes; D012997:Solvents; D006859:Hydrogen; D005479:Flurazepam; D004121:Dimethyl Sulfoxide