The Degradation Chemistry of Prasugrel Hydrochloride: Part 1—Drug Substance

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

“…In general, PRA as the higher functionalized compound shows a much more complex degradation profile with four main degradants. Known products PRA-DP-1 , PRA-DP-2 , and PRA-DP-3 obtained from forced oxidative degradation of the PRA containing drug Efient in the solid-state resemble those reported before in solution studies . However, mechanochemical oxidative degradation produces a much less complex degradation profile compared to most oxidation reactions performed in solution.…”

“…Efient is a highly active platelet inhibitor drug, containing 10 mg of PRA as API. Its impurities have been identified, and the degradation behavior in solution has been studied by several groups in the past. − An extensive study by Jansen and co-workers includes the solid-state stress testing of PRA upon prolonged exposure to elevated temperature at high and low relative humidity (RH), also under photochemical conditions. While the compound is stable under the stress conditions of heat and light at low humidity, heating and an increase in humidity (60 °C/75% RH) are reported to result in approximately 27% degradation after 28 days with the main products showing either oxidation at the thiophene moiety or hydrolytic cleavage of the oxidation products.…”

“…While the compound is stable under the stress conditions of heat and light at low humidity, heating and an increase in humidity (60 °C/75% RH) are reported to result in approximately 27% degradation after 28 days with the main products showing either oxidation at the thiophene moiety or hydrolytic cleavage of the oxidation products. Oxidative degradation in solution was studied using a variety of different oxidants, producing a wide range of new degradation products, derived from simple oxidation of the thienopyridine fragment (e.g., PRA-DP-2 , Figure ), subsequent cleavage of the API structure (e.g., PRA-DP1 and PRA-DP-3 ), or selective hydrolysis of the acetyl-thiophene fragment …”

“…Oxidative degradation in solution was studied using a variety of different oxidants, producing a wide range of new degradation products, derived from simple oxidation of the thienopyridine fragment (e.g., PRA-DP-2, Figure 5), subsequent cleavage of the API structure (e.g., PRA-DP1 and PRA-DP-3), or selective hydrolysis of the acetyl-thiophene fragment. 33 Forced oxidative degradation of PRA in a formulation was tested using our established procedure using three tablets of Efient. After a milling time of 15 min, four main products could be identified by HPLC (Figure 5) and LC-MS (Figures S14− S16).…”

“…Known products PRA-DP-1, PRA-DP-2, and PRA-DP-3 obtained from forced oxidative degradation of the PRA containing drug Efient in the solid-state resemble those reported before in solution studies. 33 However, mechanochemical oxidative degradation produces a much less complex degradation profile compared to most oxidation reactions performed in solution. The formation, characterization and isolation of a chlorinated oxidation PRA-DP-4 product was not reported to date and shows the power of our highly efficient mechanochemical approach.…”