Supplementing pharmaceutical analysis techniques using radiotracers.
Radiolabeled compounds can be used for alleviating the degradation pathways and mass balance of drug products in the solid formulation, because it provides a very sensitive and specific method of locating and measuring particular compounds. The present study utilizes this methodology on levormeloxifene-a partial oestrogen receptor agonist-in the solid dosage form. It demonstrates how radiotracers can be used as a supplement to conventional analytical methods to investigate the degradation pathways and mass balance of drug substances as well as how they can be useful to cross validate the traditional analytical methods developed for the determination of uniformity of content, assay, and purity. To decrease the study time, pilot studies-in which the product was stored at high pressures of molecular oxygen and elevated temperatures-were performed. Conditions mimicking the degradation processes taking place under standard storage conditions of the drug substance were found, and these super-enhanced stress conditions were applied. The study time was thereby dramatically decreased. The produced degradation products were studied by liquid chromatography with mass spectrometric detection. The most important degradation pathway was ascribed to the oxidation of the pyrrolidine nitrogen atom in levormeloxifene to an N-oxide derivative of the drug substance.
Lützhøft
Hans-Christian Holten
HC
CMC Development, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark.
Foged
Christian
C
Rasmussen
Stella R
SR
Lehmann
Søren
S
Olsen
Henrik
H
D004340:Drug Contamination / Q000517:prevention & control; D004364:Pharmaceutical Preparations / Q000032:analysis*; D011849:Radioactive Tracers; D013056:Spectrophotometry, Ultraviolet / Q000379:methods; D013678:Technology, Pharmaceutical / Q000379:methods*
D004364:Pharmaceutical Preparations; D011849:Radioactive Tracers