Applying Material Science Principles to Chemical Stability: Modelling Solid State Autoxidation in Mifepristone Containing Different Degrees of Crystal Disorder

Ball-milling and harsh manufacturing processes often generate crystal disorder which have practical implica-tions on the physical and chemical stabilities of solid drugs during subsequent storage, transport, and han-dling. The impact of the physical state of solid drugs, containing different degrees/levels of crystal disorder, on their autoxidative stability under storage has not been widely investigated. This study investigates the impact of differing degrees of crystal disorder on the autoxidation of Mifepristone (MFP) to develop a predic-tive (semi-empirical) stability model. Crystalline MFP was subjected to different durations of ambient ball milling, and the resulting disorder/ amorphous content was quantified using a partial least square (PLS) regression model based on Raman spectroscopy data. Samples of MFP milled to generate varying levels of disorder were subjected to a range of (accelerated) stability conditions, and periodically sampled to examine their recrystallization and degradation extents. Crystallinity was monitored by Raman spectroscopy, and the degradation was evaluated by liquid chromatography. The analyses of milled samples demonstrated a com-petition between recrystallization and degradation via autoxidation of MFP, to different extents depending on stability conditions/exposure time. The degradation kinetics were analyzed by accounting for the preced-ing amorphous content, and fitted with a diffusion model. An extended Arrhenius equation was used to pre-dict the degradation of stored samples under long-term (25 & DEG;C/60% RH) and accelerated (40 & DEG;C/75% RH, 50 & DEG;C/ 75% RH) stability conditions. This study highlights the utility of such a predictive stability model for identify-ing the autoxidative instability in non-crystalline/partially crystalline MFP, owing to the degradation of the amorphous phases. This study is particularly useful for identifying drug-product instability by leveraging the concept of material sciences.& COPY; 2023 The Authors. Published by Elsevier Inc. on behalf of American Pharmacists Association. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

Automated summary

Ball-milling and harsh manufacturing processes can lead to crystal disorder in solid drugs, affecting their stability during storage, transport, and handling. This study investigates the impact of crystal disorder on the autoxidation of Mifepristone (MFP) and develops a predictive stability model. The study highlights the utility of the model in identifying autoxidative instability in non-crystalline and partially crystalline MFP, contributing to the field of material sciences.