ANYL 130 |
| Cholesterol-lowering statins are among the most frequently prescribed drugs for reducing morbidity and mortality related to coronary heart disease. The active forms of all the hydroxymethylglutaryl (HMG)-CoA reductase inhibitors share a common dihydroxy-heptanoic or heptenoic acid chain that undergo various types of degradation. Here we discuss the forced degradation of a candidate discovered at BMS, which undergoes significant degradation under acidic (HCl) conditions leading to racemization of a chiral alcohol as well as lactonization. Degradation was also observed under UV light conditions where an intramolecular rearrangement forming a carbocyclic ring gave two diastereomeric degradants. Under radical oxidative conditions oxidation to an enone degradant is observed. The structures of the degradants and their chemistry will be outlined, along with the impact on the early stages of development. This study was used to develop a stability indicating HPLC method for both the API and the drug product. Further discussion on how column screening demonstrated that the YMC pro-C18, 3micron, 150 x 4.6mm in the presence of trifluoroacetic acid modified mobile phase gave superior resolution of a critical pair and that the addition of methanol to the acetonitrile/water mobile phase allowed for the separation of an overlapping pair of impurities. |
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General Papers
7:00 PM-9:00 PM, Sunday, 10 September 2006 Moscone Center -- Hall D, Poster
Division of Analytical Chemistry |