Bulk and Surface Conformations in Solid-State Lovastatin: Spectroscopic and Molecular Dynamics Studies

Conformational flexibility in molecules can give rise to a range of functional group terminations at crystal surfaces and dynamic disorder in the bulk. In this work, we explore the conformational behavior of the drug molecule lovastatin in the crystallographically disordered solid and at crystal surfaces through a combination of computational modeling and spectroscopy. Gas-phase and periodic quantum-chemical calculations are used to study the potential energy surface associated with rotatable bonds to examine the disorder in bulk. These calculations are combined with vibrational and X-ray photoelectron spectroscopy measurements to obtain insight into the conformations in bulk and at the surface. Our MD simulations show that the bulk disorder is driven by cooperative motion of the butyl group on the S-butanoate moiety along one crystallographic direction beyond a unit cell. The calculations show that the O-H group can rotate relatively freely between two low-energy conformers in the gas phase but is locked in position by intermolecular H-bonding interactions in the bulk crystal, and we find tentative spectroscopic evidence for the second conformer being present at the surface. We also comment on the relative utility of these different techniques for studying molecular conformation in bulk and at surfaces and highlight possible areas for future developments