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ABBV-167, a phosphate prodrug of BCL-2 inhibitor venetoclax, was recently progressed into the clinic as an alternative means of reducing pill burden for patients in high-dose indications. The dramatically enhanced aqueous solubility of ABBV-167 allowed for high drug loading within a crystalline tablet and, when administered in phase I clinical study, conferred venetoclax exposure commensurate with the equivalent dose administered as an amorphous solid dispersion. In enabling the progression into the clinic, we performed a comprehensive evaluation of the CMC development aspects of this beyond the rule of five (bRo5) prodrug. Adding a phosphate moiety resulted in excessively complex chemical speciation and solid form landscapes with significant physical-chemical stability liabilities. A combination of experimental and computational methods including microelectron diffraction (MicroED), total scattering, tablet colorimetry, finite element, and molecular dynamics modeling were used to understand CMC developability across drug substance and product manufacture and storage. The prodrug's chemical structural characteristics and loose crystal packing were found to be responsible for the loss of crystallinity during its manufacturing, which in turn led to high solid-state chemical reactivity and poor shelf life stability. The ABBV-167 case exemplifies key CMC development challenges for complex chemical matter such as bRo5 phosphate prodrugs with significant ramifications during drug substance and drug product manufacturing and storage.

Rationale: Nitrosamines are a class of mutagenic substances that can display high carcinogenic potential. New chemical entities may have the potential to form unique nitrosamines specific to the drug substance. It is therefore essential to understand the gas-phase fragmentation behavior of nitrosamine compounds to enable the development of analytical methods to characterize novel nitrosamine compounds., Methods: The gas-phase fragmentation behavior of eight model nitrosamine compounds representing the common substructures seen in many small molecule pharmaceutical compounds was studied with positive electrospray ionization tandem mass spectrometry (ESI-MS/MS). The fragmentation patterns of these compounds under various collision parameters available in commercially available mass spectrometers were studied., Results: Protonated nitrosamine compounds produced diagnostic fragment ions upon MS/MS. Three primary structure-dependent fragmentation pathways were observed. The first pathway involves the loss of 30 Da which corresponds to the loss of the NO radical from the protonated nitrosamine compound (Group 1). The second and third fragmentation pathways, which have not been reported for nitrosamine compounds, proceed via the loss of H 2 O from the protonated nitrosamine compound (Group 2), and elimination and a loss of 46 Da (loss of NH 2 NO) from the nitrosamine compound (Group 3)., Conclusions: Results presented in this work provide an overview of the gas-phase fragmentation patterns of nitrosamine compounds and may be useful in identifying novel nitrosamine compounds in complex matrices., (© 2022 John Wiley & Sons Ltd.)