Current State-of-the-art In-house and Cloud-Based Applications of Virtual Polymorph Screening of Pharmaceutical Compounds: A Challenging Case ofAZD1305

We demonstrate the successful application of the state-of-the-art AstraZeneca in-house and XtalPi cloud-based virtual polymorph screening workflows in support of stable form selection of crystalline oxabispidine AZD1305, a pharmaceutical compound. Experimental solid form screening had found two polymorphic forms, A and B, with physical stabilities that appeared to be extremely close at ambient temperature. Such observation may make experimental and in silico support of the solid form selection a challenging task. Both computational approaches correctly predicted the ranking and geometry of the stable form B at 0 K. This level of information would be important and sufficient for project support at the late discovery stage. However, metastable form A was predicted by both workflows to be considerably less stable than form B, separated by multiple virtual forms in the lattice energy landscapes. In order to account for the experimentally observed close physical stabilities of forms A and B at ambient temperature, calculation of the free-energy landscape was performed using pseudo-supercritical path method. This allowed the demonstration that, while form B is significantly more stable at 0 K, the two forms display a very close physical stability at ambient temperature. The current work highlights the importance of using advanced virtual polymorph screening to get a more comprehensive insight into identifying the most stable form of a pharmaceutical compound under different experimental conditions.