Purpose <p>To probe the formation mechanism of <i>N</i>-despropyl ropinirole, an oxidative degradant in ropinirole hydrochloride extended-release tablets.</p> Methods <p>Forced degradation studies were employed to investigate the mechanism by treating ropinirole API with H₂O₂ and AIBN, respectively, and the samples analyzed by high resolution LC-QTOF-MS. Meanwhile, the samples from the forced degradation of the extended-release tablets were analyzed by GC-QTOF-MS. The proposed mechanism was supported by an H₂¹⁸O isotope experiment. Lastly, API-excipient compatibility studies were conducted to evaluate the impact of the excipients on the formation of <i>N</i>-despropyl ropinirole.</p> Results <p>The growth trend of <i>N</i>-despropyl ropinirole in the accelerated stability study was similar to that observed in the forced degradation of ropinirole hydrochloride treated with AIBN, but vastly different from that observed in the forced degradation with H₂O₂. The forced degradation using isotope labelled H₂¹⁸O showed that ¹⁸O was incorporated into propionaldehyde, the volatile co-degradant in the formation of <i>N</i>-despropyl ropinirole. The API-excipient compatibility studies indicated that <i>N</i>-despropyl ropinirole was formed gradually in the presence of CMC-Na and HPMC, respectively.</p> Conclusions <p>Degradation of ropinirole in the ropinirole hydrochloride extended-release tablets is most likely to proceed via a free radical-mediated oxidative pathway, rather than a nucleophilic oxidative pathway. The forced degradation experiment using H₂¹⁸O is consistent with the proposed free radical-mediated degradation mechanism. The source of the free radicals seems to originate from the two excipients, CMC-Na and HPMC. The results obtained in the current study would be quite beneficial for further improvement of the drug product in terms of controlling its major degradation pathway.</p>