Development of a residual solvent test for bulk alpha-phenyl-1-(2-phenylethyl)-piperine methanol using headspace sampling.

An automated static headspace gas chromatographic method for the determination of residual solvents in the bulk drug substance alpha-phenyl-1-(2-phenylethyl)-piperine methanol, a serotonin 5-HT2 receptor antagonist, is evaluated. The method 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 acetone, ethyl acetate, methanol, and methyl ethyl ketone in the range of 0.05% to 1.0% (weight-per-weight or w/w) to verify the accuracy of this method; these four solvents are the most likely residual volatiles used in the production of the drug substance. These data and other aspects of the development of this test method are discussed.