A small molecule drug substance faced significant challenges due to its limited stability at elevated temperatures and low solubility in various organic solvents. These issues complicated the crystallization process and made it difficult to fit in the manufacturing equipment train. Initially, the production process required high solvent volumes, leading to increased waste generation and reduced product throughput. Additionally, the lack of particle size control posed a risk for downstream drug product processing. Through process development and multiple manufacturing campaigns, the process was refined to develop a more robust and sustainable long-term solution with excellent control of particle properties while reducing solvent usage by more than half. This was achieved by employing a ternary solvent system that leveraged synergistic solubility effects for crystallization development. Enhanced particle and form control were attained by implementing wet milling and humidified drying techniques respectively. High-throughput experimentation (HTE), modeling, and online process analytical technology (PAT) tools, such as Blaze, were effectively utilized to improve process understanding and scalability. As a result, a more robust and sustainable crystallization process for the small molecule pharmaceutical was developed and successfully scaled up, ensuring supply and meeting regulatory filing requirements.
