Structural elucidation of two novel degradants of lurasidone and their formation mechanisms under free radical-mediated oxidative and photolytic conditions via liquid chromatography-photodiode array/ultraviolet-tandem mass spectrometry and one-dimensional/two-dimensional nuclear magnetic resonance spectroscopy.

Lurasidone is an antipsychotic drug clinically used for the treatment of schizophrenia and bipolar disorder. During a mechanism-based forced degradation study of lurasidone, two novel degradation products were observed under free radical-mediated oxidative (via AIBN) and solution photolytic conditions. The structures of the two novel degradants were identified through an approach combining HPLC, LC-MSn (n = 1, 2), preparative HPLC purification and NMR spectroscopy. The degradant formed under the free radical-mediated condition is an oxidative degradant with half of the piperazine ring cleaved to form two formamides; a mechanism is proposed for the formation of the novel N,N'-diformyl degradant, which should be readily applicable to other drugs that contain a piperazine moiety that is widely present in drug molecules. The degradant observed under the solution photolytic condition is identified as the photo-induced isomer of lurasidone with the benzisothiazole ring altered into a benzothiazole ring.

Structure Elucidation and Mechanistic Study of a New Dimeric Degradant in Ropinirole Hydrochloride Extended-Release Tablets.

PURPOSE: The goal of the study was to elucidate the structure of a new degradant (1,3'-Dimer), generated in the stability testing of ropinirole extended-release tablets, and the formation mechanism of 1,3'-Dimer and its isomer (3,3'-Dimer). METHODS: The strategy of combining LC-PDA/UV-MSn (n = 1, 2) and NMR in conjunction with mechanism-based forced degradation study was employed to identify the structure of the unknown degradant and the formation mechanism of this dimeric degradant as well as its isomer, 3,3'-Dimer. The forced degradation was conducted by treating ropinirole API with formaldehyde under alkaline catalysis. A compatibility study between ropinirole and lactose was also performed. RESULTS: The degradant was isolated from the forced degradation sample and characterized by LC-PDA/UV-MSn as well as NMR measurement. The impurity was identified as a new dimeric degradant of ropinirole connected by a methylene bridge via the 1- and 3'-position of each ropinirole unit (i.e., 1,3'-Dimer of ropinirole), which is an isomer of a known dimeric degradant of ropinirole, namely 3,3'-Dimer. CONCLUSIONS: The newly occurred unknown degradant in ropinirole extended-release tablets was elucidated as the methylene-bridged 1,3'-Dimer of ropinirole. Based on the mechanistic study, 1,3'-Dimer and its isomer (3,3'-Dimer) were both formed by the reaction of ropinirole with residual formaldehyde present or formed in lactose, a main excipient of the formulation.

Solution degradant of mirabegron extended release tablets resulting from a Strecker-like reaction between mirabegron, minute amounts of hydrogen cyanide in acetonitrile, and formaldehyde in PEG during sample preparation.

During the related substances testing of mirabegron extended release tablets, an unknown peak was observed in HPLC chromatograms in a level exceeding the identification threshold. By using a strategy that combines LC-PDA/UV-MSn with mechanism-based stress studies, the unknown peak was rapidly identified as cyanomethyl mirabegron, a solution degradant that is caused by a Strecker-like reaction between the API, formaldehyde (an impurity in PEG), and HCN (an impurity in HPLC grade acetonitrile). The mechanism of the solution degradation chemistry was verified by stressing mirabegron with formaldehyde and trimethylsilyl cyanide (TMSCN, a synthetic reagent that generates HCN upon contact with water), in which the secondary amine group of mirabegron first reacts with formaldehyde to form the iminium ion intermediate; the latter then undergoes a nucleophilic attack by cyanide to yield the cyanomethyl mirabegron. The structure of the impurity was further confirmed through the synthesis of the impurity and subsequent structure characterization by 1D and 2D NMR. Due to the ubiquitous presence of formaldehyde in pharmaceutical excipients (e.g., PEG and polysorbate) and trace amount of HCN in HPLC grade acetonitrile, this type of solution degradation would likely occur in sample preparations of pharmaceutical finished products containing APIs with primary and secondary amine moieties. In a GMP environment, such an event may trigger undesirable out-of-specification (OOS) investigations; the results of this paper should help resolve such OOS investigations or even prevent these events from happening in the first place.

"Ghost peaks" of ezetimibe: Solution degradation products of ezetimibe in acetonitrile induced by alkaline impurities from glass HPLC vials.

Unpredictable degradation of Ezetimibe solutions in pure acetonitrile occurs when they are stored in glass HPLC vials. The occurrence of the two main degradation peaks and one minor peak was unpredictable at the time of each sample preparation and over time, it appeared that approximately 15% of the sample solutions in glass HPLC vials would eventually show the degradation peaks. Once the degradation peaks occurred in a particular vial, typically within 24h, they would keep growing until reaching a total yield of about 4-5%. Through a comprehensive investigation, it is determined that the solution degradation is caused by a base-catalyzed process, during which ezetimibe undergoes (1) dimerization to form two dimeric impurities, which have not been reported in the literature, and (2) to a less degree, isomerization to produce an isomeric impurity that has been reported before.