(568b) Accelerated Early-Stage Enabling API Crystallization Process Development and Scale-up
AIChE Annual Meeting
2021 Annual Meeting
Crystallization Process Development
Thursday, November 11, 2021 - 8:24am to 8:45am
Swift crystallization solvent selection was aided by a combination of in-silico modeling using COSMO quantum chemistry software in conjunction with experimental UHPLC based solubility measurements. Selection of a suitable solvent-antisolvent system was further informed using DynoChem®, which was leveraged to generate full solubility curves over a range of temperatures and compositions with limited experimental data. Leveraging these tools is often essential in early-stage process development due to limited material availability. A favorable solubility profile for a given composition was identified, and a simple cooling crystallization was designed to afford high yield and purity. Material lean experiments using a variety of process analytical technologies (PAT) were designed to determine the metastable zone width and explore seeding conditions (seed load and supersaturation ratio) to ensure consistent crystal form control while avoiding oiling out. A complex form landscape during filtration and drying was mapped with DSC/TGA/MS and PXRD and navigated through to ensure the physical properties of the API were preserved during filtration, washing, and drying. Carefully tailored displacement washes were developed and leveraged to avoid crystal form change. A terminal wet milling and thermocycling process was also developed to control crystal surface area in conjunction with appropriate drying process understanding to achieve target specifications in the lowest cycle time. The process was successfully scaled-up to kilo scale to enable the GLP toxicity study.
All authors are employees of AbbVie and may own AbbVie stock. AbbVie sponsored and funded the study; contributed to the design; participated in the collection, analysis, and interpretation of data, and in writing, reviewing, and approval of the final publication.