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

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 Ticlopidin-neuraxpharm 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.

Synthesis and coordination chemistry of the PPN ligand 2-[bis(diisopropylphosphanyl)methyl]-6-methylpyridine.

The synthesis and crystal structure of the multidentate PPN ligand 2-[bis(diisopropylphosphanyl)methyl]-6-methylpyridine (L), C19H35NP2, are described. In the isostructural tetrahedral Fe and Co complexes of type LMCl2 (M = Fe, Co), namely {2-[bis(diisopropylphosphanyl)methyl]-6-methylpyridine-κ2P,N}dichloridoiron(II), [FeCl2(C19H35NP2)], and {2-[bis(diisopropylphosphanyl)methyl]-6-methylpyridine-κ2P,N}dichloridocobalt(II), [CoCl2(C19H35NP2)], the ligand adopts a bidentate P,N-coordination, whereas in the case of the octahedral Mn complex {2-[bis(diisopropylphosphanyl)methyl]-6-methylpyridine-κ2P,P'}bromidotricarbonylmanganese(I), [MnBr(C19H35NP2)(CO)3], the ligand coordinates via both P atoms to the metal centre.