RESOLUTION OF THE CO-ELUTING IMPURITY 3,4-DIHYDRO-3,3-DIMETHYLISOQUINOLINE IN PHENTERMINE BASE USING HPLC-UV PHOTODIODE-ARRAY DETECTION FOLLOWED BY IDENTIFICATION VIA GC-(EI-MS())

In the course of process development for phentermine base, samples wer e observed to fail the UV specification. Analysis using the HPLC purit y profile method did not yield unusual results. However, re-analysis u sing UV-photodiode array detection indicated the presence of an impuri ty that almost exactly co-elutes with the phentermine peak. Comparison of these samples with previously manufactured lots known to pass the UV test, along with area comparison of the impurity, permitted its det ermination by GC. Previous efforts had tentatively identified this pea k 2,3,3 trimethylindolenine. Further evaluation using GC(EI+)MS confir med the identity of the peak as 3,4-dihydro-3,3-dimethylisoquinoline, formed via a Bischler-Napieralski type reaction (cyclodehydration of a cyl derivatives). The impurity was eliminated from the process by mini mizing those factors that contribute to its formation. Assay of the (s ic).