(670f) Leveraging Retrograde Solubility for Crystallization Process Optimization

Retrograde solubility is an uncommon phenomenon where the solubility of the solute decreases with increase in temperature. In this work, we present the crystallization process design of an API with retrograde solubility. While the inverse dependence of temperature on the solubility in different solvents was identified early on in process development, this phenomenon was not exploited in the enabling route to design the crystallization. Instead, an isothermal antisolvent crystallization was initially designed to isolate the API. To optimize the API manufacturing process, the crystallization process was redesigned in a different solvent system while leveraging the retrograde solubility of the API. Alongside, the API step chemistry was also re-designed to better integrate into the crystallization solvent system with a lower impurity burden, while also avoiding an aqueous work-up and a subsequent solvent-swap. Overall, the optimized process improved the purity and process mass index, while reducing the number of manufacturing steps. This work highlights how retrograde solubility can be leveraged to design an optimal crystallization process.

Disclosure:

Akshay Korde, Kaid Harper, David Dhanraj, Jie Chen and Nandkishor Nere are employees of AbbVie. Moussa Boukerche is a former employees of AbbVie. All authors 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.