MULTINUCLEAR NMR (H-1, C-13 AND F-19) SPECTROSCOPIC REEXAMINATION OF THE SOLVOLYTIC BEHAVIOR OF FLURAZEPAM DIHYDROCHLORIDE

The dissolution of reference and archival samples of flurazepam dihydr ochloride (2) was studied in DMSO-d(6) and in D2O by H-1-, C-13- and F -19-NMR spectroscopy to identify and distinguish solvated species of t he parent drug (2), the ''benzophenone'' (4) and glycine (5) hydrochlo ride degradation products. In DMSO-d(6) for most samples, only the rin g intact form (2) could be detected by C-13-NMR whereas the inherently greater sensitivity of F-19-NMR allowed detection of initial trace am ounts (<1%) of the open:ring form (3). F-19-NMR spectroscopy also affo rded the best means of quantifying the various entities in solution, i ncluding the increase towards equilibrium levels of the open-ring enti ty and detection/quantitation of a new equilibrium species, possibly t he cis/trans rotamer of the open-chain entity (3). Various chemical sh ifts for flurazepam dihydrochloride and USP flurazepam related referen ce standards C and F are reported for DMSO-d(6) solutions, The bases f or H-1- and F-19-NMR assay of DMSO-d(6) solutions of (2) for (4) are d iscussed with comparative data. The solvation characteristics of (2) i n D2O at 0 and 27 degrees C were found to be too complex to follow by C-13-NMR; however, F-19-NMR studies at these temperatures permitted on e to clearly discern that no additional formation of entity (4) occurr ed beyond whatever initial levels were present in degraded samples whi le 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.