Co-milling of glass forming ability class III drugs: Comparing the impact of low and high glass transition temperatures
Year: 2025
Type: article
Abstract: With an increasing focus on sustainable technologies in the pharmaceutical industry, milling provides a solvent-free approach to improve drug dissolution. Milling of drugs with an excipient offers additional opportunities to achieve supersaturation kinetics. Therefore, this work aims to present insights of co-milling fenofibrate and apremilast, two good glass formers with low and high glass transition temperatures (T g s) respectively. Drugs were co-milled with croscarmellose sodium for various process durations followed by thermal analysis, investigation of crystallinity, surface area and dissolution. The dissolution enhancement of the low-T g glass former fenofibrate highly correlated with the process-induced increase in surface area of co-milled systems (R 2 = 0.96). In contrast, the high-T g glass former apremilast lost its crystalline order gradually after ≥ 10 min of co-milling, and favourable supersaturation kinetics during biorelevant dissolution testing were observed. Interestingly, the melting point of co-milled apremilast decreased and linearly correlated with the highest measured drug concentration (c max ) during in vitro dissolution (onset temperature R 2 = 0.98; peak temperature R 2 = 0.96). The melting point depression remained stable after 90 days for apremilast, whereas fenofibrate co-milled for 20 min or more showed an increase in melting point upon storage. This study demonstrated that co-milling with croscarmellose sodium is ideally suited to good glass formers with a high T g . The melting point depression is thereby proposed as an easily accessible critical quality attribute to estimate likely dissolution performance of drugs in dry co-milled formulations.
Authors: Nicolas Pätzmann, Josef Beránek, Brendan T. Griffin, Martin Kuentz, Patrick J. O'Dwyer
Language: English
Subfield: Pharmaceutical Science
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,070
OpenAlex ID: W4408783461