Evaluation of a headspace-GC method for residual solvents in a serotonin 5-HT3 antagonist compound.

A static headspace gas chromatographic method is developed and evaluated for the quantitation of residual 2-propanol, methanol, and toluene in bulk (2alpha, 6alpha, 8alpha, 9alpha beta)-octahydro-3-oxo-2,6-methanon-2H-quinolizin-8-yl-1H-indole-3-caboxylate methanesufonate hydrate, a serotonin 5-HT3 receptor antagonist drug compound. This method is accurate and precise, and it includes the use of 1-propanol as an internal standard. The gas chromatographic conditions utilize a dimethylpolysiloxane phase (SPB-1) capillary column and a flame ionization detector. Validation of this test method includes a recovery study of known levels of the three target analyte solvents to verify the accuracy of this method, because these solvents were used in the recrystallization and synthesis of all current and future lots of the bulk drug. The tested range is 0.05% to 1.0% (w/w) for 2-propanol and methanol and 0.01% to 0.10% (w/w) for toluene. Mean recovery of all spikes is 107% (w/w) of theory for methanol (n = 15) and 101% (w/w) for 2-propanol. Toluene mean recovery of all spikes is 98% (w/w) of theory within the tested range (n = 6). These data and other facets of the development of this headspace method are discussed.