Mechanoactivation as a Tool to Assess the Autoxidation Propensity of Amorphous Drugs

Abstract

Mechanoactivation has attracted considerable attention in the pharmaceutical sciences due to its ability to generate amorphous materials and solid-state synthetic products without the use of solvent. Although some studies have reported drug degradation during milling, no studies have systematically investigated the use of mechanoactivation in predicting drug degradation in the solid state. Thus, this work explores the autoxidation of drugs in the solid state by comilling amorphous mifepristone (MFP):polyvinylpyrrolidone vinyl acetate (PVPVA) and amorphous olanzapine (OLA):PVPVA. MFP was amorphized by ball milling and OLA by quench cooling techniques. Subsequently, comilling the amorphous drugs in the presence of a 10-fold weight ratio of PVPVA (the excipient containing reactive free radicals) was performed at several milling frequencies to identify the kinetics of mechano-autoxidation over milling durations. Overall, milling led to the degradation of up to 5% drug in the solid state. The autoxidation mechanism was confirmed by performing a stress study in the solution at 50 °C for 5 h, by using a 10 mM azo-bis(isobutyronitrile) (AIBN) as a stressing agent. By deconvoluting the effect of milling frequency and the energy on the extent and kinetics of milling-induced autoxidation of amorphous drugs, it was possible to fit an extended Arrhenius model that allowed extrapolation of mechanoactivated degradation rates (K m) to zero milling frequencies. Further, the autoxidation rates of drugs stored at high temperatures were observed to follow an Arrhenius behavior. A good degree of agreement was observed between the model predictions obtained by mechanoactivation (K m) to the reaction rates observed under accelerated temperatures. Additionally, the impact of adding an antioxidant (e.g., butylated hydroxytoluene) to the mixture during comilling was also examined. This study can be helpful in evaluating the stability of amorphous solids stored in accelerated (non-hermetic) conditions, in screening solid-state autoxidation propensity of drugs, and for the rational selection of antioxidants.

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

“…PRA-DP-4 is formed as a mixture of two diastereomers, showing characteristic overlapping doublet resonances for the remaining CH proton at the thiophenone unit (6.14 ppm) and the bridging methine proton at 4.90 ppm. In the 19 ppm. This result of chloride incorporation is reminiscent of previous studies of oxidative halogenation of TIC and CLP in solution.…”

“…Embracing the enormous potential of mechanochemistry for various fields of organic and inorganic synthesis, − materials chemistry, and pharmaceutical sciences, , we have therefore recently developed a new method that uses mechanochemistry for the modeling of oxidative degradation processes in APIs (Figure b). , In general, several approaches were developed for such studies, including the use of H 2 O 2 , azoalkanes, radical initiators, or transition metals, covering several types of oxidations, i.e., one- or two-electron oxidation or free-radical oxidation . The mechanochemical oxidation of small organic molecules such as 5-hydroxymethyl furfural and lignin β-O-4 model compounds was reported before. , Paudel and co-workers have recently applied mechanoactivation to evaluate the autoxidation propensity of amorphous drugs …”

“…17,18 Paudel and co-workers have recently applied mechanoactivation to evaluate the autoxidation propensity of amorphous drugs. 19 Our previous work used 14 Clopidogel hydrogen sulfate (CLP), a compound present in antiplatelet drugs, as a thienopyridine containing model compound. Different degradation products could be selectively obtained by ball-milling in short reaction times of less than 15 min.…”