Integration of a model-driven workflow into an industrial pharmaceutical facility: supporting process development of API crystallisation

Abstract

Developing crystallisation processes in the pharmaceutical industry is material and resource intensive due to the large design space, i.e. many different process parameters and combinations thereof. Furthermore, small scale experimental results don't necessarily translate when volume is scaled up due to changes in liquid flow, mixing and heat transfer surface area. However, indications that knowledge-driven resource reduction on a small scale is possible and results may be worth investigating at larger scales. Therefore, this study presents and evaluates a knowledge-driven workflow which achieves its goal of reducing the necessary resources previously required to develop a crystallisation process suitable for commercial manufacture in a pharmaceutical setting. By following this workflow, thermodynamic and isothermal kinetic data for the cooling crystallization of (3S,5R)-3-(aminomethyl)-5-methyl-octanoic acid (PD-299685) within an 8-week timeframe were obtained. Moreover, the workflow was expanded to include isothermal kinetic parameters from a 50-fold scaled-up cooling crystallisation, as well as antisolvent and seeded crystallisation of PD-299685. The systematic and standardised data collection facilitated by this workflow enabled the design and optimisation of the PD-299685 crystallisation process. The proposed scalable industrial crystallisation route for PD-299685 combines cooling and antisolvent techniques, offering a wide metastable zone width to facilitate speck-free filtration and effective seeding. This approach allows for control over product quality, resulting in particles with a desired aspect ratio of 0.766 and a d(v,90) value of 234 μm through wet milling. These parameters align with the proposed API material target specifications for solid oral dosage form quality, specifically oral bioavailability and content uniformity, and efficient drug product manufacture all whilst demonstrating a significant reduction in material usage.