(672e) Development of a Crystallization Process to Prevent Oiling and Optimize Physical Properties of a Drug Substance

The need for new medications has necessitated increasing complexity in the molecular structure of modern pharmaceutical drug substances. As these molecules become more complex, isolating them in crystalline form becomes increasingly difficult due to challenges such as liquid-liquid phase separation (LLPS), poor desaturation kinetics, and poor particle morphology. These challenges can have negative consequences for manufacturing processes at scale resulting in inconsistent operational and quality attributes including: impurity rejection, powder properties, and crystal form. In this work we discuss an industrial case study for a challenging active pharmaceutical ingredient (API) crystallization which exhibits LLPS, slow desaturation kinetics, poor powder properties, and inconsistent form.

We describe development of the crystallization process using a comprehensive experimental and modeling approach which includes: solubility and salt screening, upstream process modification, and crystallization parameter optimization (addition rates, seed loading, temperature cycling, etc.). LLPS of the API could be avoided through proper pH control before crystallization which was verified by modeling of the pKa of various basic sites on the compound and corresponding modification of upstream processing. Desaturation kinetics and morphology of the compound was tracked with PAT (FBRM, IR) which was utilized to model the kinetics of the crystallization. Modeling showed slow growth and that nucleation accounted for most desaturation. We optimized an unseeded crystallization by varying anti-solvent addition rates and temperature cycling to tune the physical properties of the drug substance while maintaining high yield. Finally, we utilized a recrystallization to achieve consistent crystal form.