(568b) Accelerated Early-Stage Enabling API Crystallization Process Development and Scale-up

Development of crystallization, filtration/washing, and drying processes is an essential cornerstone of delivering quality Active Pharmaceutical Ingredient (API) in the pharmaceutical industry. During early-stage development, rapid timelines and the need to generate high quality API to enable GLP toxicity studies and Phase I clinical trials necessitate rapid and targeted data rich experimentation to develop robust and scalable processes. While early-stage crystallization development often falls upon the chemists, early intervention with an engineering and scalability-focused mindset can significantly reduce the development burden later in the pipeline. Such development efforts on Compound A, and the enabling data-rich workflow leveraged to yield a robust crystallization, filtration, and drying process is detailed in this work. A rapid 6-week development period, followed by a successful scale up from gram to kilo scale over a subsequent two-week period enabled a GLP toxicity study to proceed for the early-stage Compound A.

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.

Disclosures:

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.