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. <i>In silico</i> 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.