Identification and structural elucidation of an oxidation product generated during stability studies of Cabergoline drug product
Cabergoline is a dopamine agonist with applications as anti-Parkinson drug and prolactin inhibitor. The cabergoline drug product Laktostop® 50 µg/mL is used in veterinary medicine for lactation suppression in cats and dogs e.g. during false pregnancy. Recently, during ongoing HPLC stability testing of Laktostop® 50 µg/mL a new oxidation product of Cabergoline was identified. A synthesis starting from Cabergoline was developed, followed by full characterization of the unknown impurity.
Highlights
- Synthesis and isolation of an oxidation product starting from cabergoline.
- Identity was demonstrated by HPLC experiments and high-resolution mass spectrometry.
- Structure elucidation by MS-MS fragmentation experiments and 1D/2D NMR analysis.
- Radical induced formation mechanism is proposed.
Preliminary HPLC and LC-MS analyses indicated the unknown impurity as mono-oxygenated product of Cabergoline (Cabergoline N-oxide) that is presumably formed with oxygen by a radical mechanism. Thus, Cabergoline was treated with oxidizing agents such as m-chloroperoxybenzoic acid to afford the desired Cabergoline-N-oxide as a byproduct. After isolation by column chromatography, NMR and LC-MS-MS studies provided evidence that oxidation occurred at the N-allyl nitrogen of Cabergoline to form Cabergoline-N-oxide.
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Degradant enrichment experiments in the drug substance and drug product
The drug product Laktostop® 50 µg/mL consists of the active ingredient cabergoline and the liquid excipient miglyol – a mixture of saturated medium-chain triglycerides, mainly composed of capric acid or caprylic acid molecules and glycerol. To elucidate the formation of the impurity in LAK different attempts were conducted. Initially, a cabergoline solution 50 µg/mL was freshly prepared and analyzed.
Tilman Lechel, Ruben Silva Otero, Andreas Springer, Anja Rutkowski, Dominik Matzkow, Johannes Zart, Tobias Hartmann, Dieter Hochhuth, Identification and structural elucidation of an oxidation product generated during stability studies of Cabergoline drug product, Journal of Pharmaceutical and Biomedical Analysis, Volume 248, 2024, 116282, ISSN 0731-7085, https://doi.org/10.1016/j.jpba.2024.116282.