(171b) Investigating the Correlation of Chemical Stability and Process Induced Disorder: A Case Study of Phosphate Prodrug of Venetoclax

Venetoclax, the first-in-class selective BCL-2 inhibitor that has transformed the treatment of chronic lymphocytic leukemia (CLL) and acute myelogenous leukemia (AML), is a complex beyond rule-of-five (bRo5) molecule with physicochemical properties that fall well outside those of typical orally bioavailable drugs. This includes high molecular weight, extremely low aqueous solubility and permeability. To improve the drug’s bioavailability, ABBV-167, a phosphate prodrug of Venetoclax with better ADME properties was evaluated. The bRo5 BCL-2 prodrug molecule has remarkably increased the solid form complexity and lead to development challenges such as excessively complex speciation, polymorphic landscapes, and significantly altered chemical and physical stabilities. In this study, a comprehensive evaluation was performed to fully assess the crystalline disorders of ABBV-167 hemi-sulfate hexahydrate that are associated to different manufacturing steps including crystallization, drying, and tablet compression. Apart from the traditional evaluation of crystallinity loss using lab X-ray powder diffraction, synchrotron-based high-resolution total scattering pair distribution function (PDF) analysis was also applied to correlate process-induced crystalline disorder with process conditions. The relationship between the degree of crystalline disorders and risk of chemical stability under stressed conditions was elucidated. We found that undesired process-induced crystallinity disorder can significantly influence the chemical stability of prodrug drug substance and further impact the shelf-life and impurity profile of drug product. The study has illustrated the importance and challenges of assessing and controlling process induced crystalline disorders for chemically labile prodrugs with complex solid form landscape.

Disclosure:

AbbVie and Genentech sponsored and funded the study; contributed to the design; participated in collection, analysis, and interpretation of data; and in writing, reviewing, and approval of the final version. All authors are employees or former employees of AbbVie. Haichen Nie is currently an employee of Merck. The authors declare no competing financial interest.