Beyond Barriers, Big Crystallization Hurdles: Atropisomerism in Beyond Rule of Five Compounds Explored by Computational and NMR Studies

Stereochemical purity, stability, and selection of a
suitable solid-state
form are pivotal factors in pharmaceutical development, particularly
for complex beyond Rule of 5 (bRo5) compounds. In this study, we explore
the intricate interplay between atropisomerism and crystallization
using two model bRo5 compounds, namely, ACBI1 and BI201335, both violating
three of four Lipinski’s rules. One of the tool compounds exhibits
Class 2 atropisomeric behavior, and the other is devoid of it. A diverse
array of crystallization methods, including solution-phase crystallization,
cocrystallization, and salt formation, were applied, revealing the
critical role of atropisomerism-induced stereochemistry in polymorphism
and nucleation outcomes. In silico torsion profile
calculations and NMR studies were employed to elucidate the rotational
energy barriers and confirm the presence or absence of atropisomerism.
This comprehensive analysis highlights the significance of understanding
stereochemical phenomena such as atropisomerism in designing and developing
bRo5 compounds. By integrating advanced analytical techniques and
crystallization strategies, this work provides novel insights into
tailoring pharmaceutical properties for next-generation therapeutics.