Mechanochemical Oxidative Degradation of Thienopyridine Containing Drugs: Toward a Simple Tool for the Prediction of Drug Stability

Abstract

The long-term stability of an active-pharmaceutical ingredient and its drug products plays an important role in the licensing process of new pharmaceuticals and for the application of the drug at the patient. It is, however, difficult to predict degradation profiles at early stages of the development of new drugs, making the entire process very time-consuming and costly. Forced mechanochemical degradation under controlled conditions can be used to realistically model long-term degradation processes naturally occurring in drug products, avoiding the use of solvents, thus excluding irrelevant solution-based degradation pathways. We present the forced mechanochemical oxidative degradation of three platelet inhibitor drug products, where the drug products contain thienopyridine. Model studies using clopidogrel hydrogen sulfate (CLP) and its drug formulation Plavix show that the controlled addition of excipients does not affect the nature of the main degradants. Experiments using drug products Ticlopidinneuraxpharm and Efient show that significant degradation occurs after short reaction times of only 15 min. These results highlight the potential of mechanochemistry for the study of degradation processes of small molecules relevant to the prediction of degradation profiles during the development of new drugs. Furthermore, these data provide exciting insights into the role of mechanochemistry for chemical synthesis in general.

Prediction of Degradation Profiles for Various Sartans under Solvent-Free Mechanochemical Conditions

“…In contrast to LOS-7 , the chlorination cannot be explained by the incorporation of a chlorine atom from the API itself. In addition, since IRB is the free base, the incorporation of the counterion, as described by Krake and co-workers for ticlopidine hydrochloride and prasugrel hydrochloride, is also not an appropriate explanation . Probably, traces of chlorine-containing reagents from the synthesis in IRB are the source for the chlorine substituent in IRB-6 . , For both IRB-5 and IRB-6 , it is assumed that the additional functional group is located in the structural part of the imidazolone ring, since fragments m / z 211.1441 (C 11 H 19 N 2 O 2 + , 0.0 ppm) and m / z 229.1102 (C 11 H 18 ClN 2 O + , 0.4 ppm) were detected and assigned, respectively (Tables S3 and S8-A).…”

“…In light of the aforementioned successful mechanochemical methods and the overall importance of APIs, we felt encouraged to strengthen both fields with the goal of enhancing and broadening the applications of mechanochemistry in the pharmaceutical industry. In this context, we recently reported the first mechanochemical degradation studies of thienopyridine using the API clopidogrel hydrogensulfate and related APIs. − These data enabled us to provide a vital degradation profile that may be designed for the prediction of API stability under realistic conditions.…”

Mechanochemical Degradation of Caffeine and Diclofenac Using Biochar of Fique Bagasse in the Presence of Al: Monitoring by Mass Spectrometry

“…Meanwhile, Yuan et al reported a mechanochemical process for the elimination of heavy metals (Cu, Pb, and Cd), polybrominated diphenyl ethers (PBDEs), and polychlorinated biphenyls (PCBs) from contaminated soils; in this work, the achieved degradation percentages varied from 85 to 95% . Likewise, the degradation of thienopyridine from three commercial drugs under MC conditions has been reported in only 15 min of treatment . According to the results of the studies described above, it can be suggested that mechanochemistry methods can degrade the emerging contaminants: caffeine and diclofenac.…”

“… 9 Likewise, the degradation of thienopyridine from three commercial drugs under MC conditions has been reported in only 15 min of treatment. 12 According to the results of the studies described above, it can be suggested that mechanochemistry methods can degrade the emerging contaminants: caffeine and diclofenac.…”

Shock-Induced Degradation of Guanosine and Uridine Promoted by Nickel and Carbonate: Potential Applications

“…Despite its applicability in a variety of fields, as in green synthetic methods [2], mechanochemistry could also be applied to the degradation of organic molecules [2,4,5]. Polymer degradation and stability studies of active pharmaceutical compounds are two major fields where mechanochemically induced degradation can be applied [4,6,7]. Many compounds contain a mechanophore, which is a portion of a molecule that follows a known mechanical perturbation [8], which could help in the elucidation of degradation mechanisms, for example, for biomolecules.…”