(92a) Development of Automated Milling Platform for Crystal Engineering

Shailesh Agrawal*, Saurin H Rawal, Jeremy Merritt

*Presenting Author

Synthetic Molecule Design and Development, Eli Lilly & Company.

Wet milling is widely used in pharmaceutical industry as a leverage to modify both; size and morphology of the final crystalline drug substance (DS) as these play a pivotal role in formulation of an appropriate drug product [1]. A common approach to modify crystal size and morphology is to use multiple thermal cycles in conjunction with milling, that involves cyclical dissolution and recrystallization steps[2]. There is a widespread adoption of autonomous reactor operations coupled with process analytical technology that helps in accelerating crystallization development but there aren’t significant inroads in extending robust automation to slurry milling. Herein, we demonstrate an autonomous milling setup paired with an automated crystallizer setup that can extend equipment utilization in an industrial setup and help develop data rich milling processes in a fashion that would aid current aggressive drug substance/ drug product development timelines.

We will discuss the development and deployment of a customized automated platform to perform milling in conjunction with thermal cycling to achieve desired improvements in the DS physical properties. Lovastatin, a commercially available DS and notorious for yielding needle shaped crystals [3] is used as a model compound to demonstrate the capabilities of the platform. We will use this compound to demonstrate the time to develop the process and corresponding improvement in physical properties.

The study will briefly discuss the efforts towards building a high-fidelity mathematical model for the combined milling and thermal cycling process. It is envisioned that coupled with a digital twin[4], the automated platform will significantly accelerate the development of an optimized milling process to achieve desired size and morphology.

References

1. Salvatori, F. and M. Mazzotti, Manipulation of Particle Morphology by Crystallization, Milling, and Heating Cycles—A Mathematical Modeling Approach. Industrial & Engineering Chemistry Research, 2017. 56(32): p. 9188-9201.
2. Wilson, D., et al., Particle engineering of needle shaped crystals by wet milling and temperature cycling: Optimisation for roller compaction. Powder Technology, 2018. 339: p. 641-650.
3. McGinty, J., et al., Effect of Process Conditions on Particle Size and Shape in Continuous Antisolvent Crystallisation of Lovastatin. 2020. 10(10): p. 925.
4. Szilágyi, B., et al., Digital Design of the Crystallization of an Active Pharmaceutical Ingredient Using a Population Balance Model with a Novel Size Dependent Growth Rate Expression. From Development of a Digital Twin to In Silico Optimization and Experimental Validation. Crystal Growth & Design, 2022. 22(1): p. 497-512.