PROFILING IMPURITIES AND DEGRADANTS OF BUTORPHANOL TARTRATE USING LIQUID-CHROMATOGRAPHY MASS-SPECTROMETRY AND LIQUID-CHROMATOGRAPHY TANDEM MASS-SPECTROMETRY SUBSTRUCTURAL TECHNIQUES

A rapid and systemic strategy based on liquid chromatography/mass spec trometry (LC/MS) profiling and liquid chromatography/tandem mass spect rometry (LC/MS/MS) substructural techniques was utilized to elucidate the degradation products of butorphanol, the active ingredient in stad ol(R) NS. This strategy integrates, in a single instrumental approach, analytical HPLC, UV detection, full-scan electrospray mass spectromet ry, and tandem mass spectrometry to rapidly and accurately elucidate s tructues of impurities and degradants. In these studies, several low-l evel degradation products were observed in long-term storage stability samples of bulk butorphanol. The resulting analytical profile include s information on five degradants including molecular structures, chrom atographic behavior, molecular weight, UV data, and MS/MS substructura l information. The degradation products formed during long-term storag e of butorphanol tartrate included oxidative products proposed as 9-hy droxy- and 9-keto-butorphanol, norbutorphanol, a ring-contraction degr adant, and Delta 1, 10 alpha-butorphanol. These methodologies are appl icable at any stage of the drug product cycle from discovery through t o development. This library of butorphanol degradants provides a found ation for future development work regarding product monitoring, as wel l as a useful diagnositc tool for new degradation products.