(82g) Scalability and Predictability of Terminal Wet Milling Processes

Active pharmaceutical ingredients delivered through oral solid dosage forms usually require tight control of purity and particle size. For robust control and scaleup, practitioners are usually interested in correlating wet milling process parameters such as rotation rate, generator types, and number of batch turnovers to particle size and particle size distribution t [1-5]. High shear environments can also induce and accelerate form interconversion [6].

This work describes a process where particle size control and form control are achieved via high-shear rotor-stator wet milling. Practical considerations as well as mechanistic models used for process design, optimization, scale-up and overall control strategy will be discussed.

References

[1] C. Luciani, E. Conder, and K. Seibert. Org. Process Res. Dev. 2015, 19, 5, 582–589.

[2] A. Harter, L. Schenck, I. Lee, A. Cote. Org. Process Res. Dev. 2013, 17, 1335– 1344

[3] J. Engstrom, C. Wang, C. Lai, J. Sweeney. Int. J. Pharm. 2013, 456, 261– 268

[4] Luciani. Org. Process Res. Dev. 2018, 22, 9, 1328–1333

[5] K. Seibert, P. Collins, C. Luciani. Chapter 30: Milling Operations in the Pharmaceutical Industry. In Chemical Engineering in the Pharmaceutical Industry: Active Pharmaceutical Ingredients, Second Edition 2019. Editors: D. am Ende and M. am Ende, pp. 861-879.

[6] R. Carrasquillo-Flores, S. Wisniewski, V. Daftary, F. Lora-Gonzalez, T. Rosenbaum, R. Wethman, M. Huang, J. Wasylyk, J. Selekman, C. Choi, B. Mack, T. Razler, and J Engstrom. Org. Process Res. Dev. 2021, 25, 4, 1028–1035.