Abstract
SY0916 has been proven to be a potent treatment agent against rheumatoid arthritis in preclinical studies and has been shown to be safe in phase I clinical trials. However, SY0916 is unstable in water, which is frequently used in pharmaceutical development processes. The degradation behaviour and stability of SY0916 in aqueous solutions were investigated at different pH levels, periods of time, and temperatures. Two degradation products (DPs) were successfully separated and characterized by liquid chromatography coupled to high-resolution tandem mass spectrometry (LC-HRMS/MS), liquid chromatography coupled to nuclear magnetic resonance with solid phase extraction (LC-SPE-NMR), and nuclear magnetic resonance (NMR). SY0916 decomposed to its α,β-unsaturated ketone in protonic solvents, and the α,β-unsaturated ketone further transformed into its alcohol form through a conjugate addition reaction in aqueous media. The results of this study indicate that the pH of the buffer solutions should be maintained between 3.0 and 3.6 for maximum SY0916 stability. Factors that affect degradation should be carefully controlled to mitigate or avoid drug decay.
Highlights
Platelet-activation factor (PAF) is considered a significant inflammatory mediator of different pathologies, including various types of inflammation [1, 2], allergy [3], and immune diseases [4, 5]
Structural characterization of the degradation products (DPs) was performed using liquid chromatography coupled to high-resolution tandem mass spectrometry (LC-HRMS/ MS), liquid chromatography coupled to nuclear magnetic resonance with solid phase extraction (LC-SPE-NMR), and nuclear magnetic resonance (NMR). e stability of SY0916 in solution was controlled by using a specific pH range and time
The results of this study provide a useful reminder to consider the conditions during SY0916 development processes, such as the dissolvent choice for analytical methods in routine assays or for pharmacokinetic studies and the solvent use in formula preparations
Summary
Platelet-activation factor (PAF) is considered a significant inflammatory mediator of different pathologies, including various types of inflammation [1, 2], allergy [3], and immune diseases [4, 5]. SY0916 ((E)-ethyl1-(5-(4-chlorophenyl)-3oxopent-4-enyl)piperidine-4-carboxylate, Figure 1), a firstin-class PAF receptor antagonist, has been proven to be highly effective for rheumatoid arthritis therapy in preclinical studies and has been shown to be safe in phase I clinical trials [6,7,8,9,10,11]. In rats with collagen-induced type II arthritis, SY0916 significantly relieved inflammation in soft tissue around the middle of joints, as observed by X-ray and pathological examination [7], and greatly decreased the serum levels of IgG, TNF-α, and IL-β [8]. Doses of up to 500 mg were well tolerated and presented no serious adverse events in the first-in-human study
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