Hydrophilic and hydrophobic interactions in the solid forms of the β-sitosterol cocrystal with propionic acid: A combined experimental and computational study

• Two new forms of β-sitosterol have been discovered, prepared and their crystal structures analyzed using DFT calculations. • β-sitosterol cocrystals stability is significantly influenced by a delicate balance of hydrophobic and hydrophilic interactions. • Hydrophobic interactions play a critical role in the structural integrity of β-sitosterol cocrystals. • Hydrophilic interactions, primarily mediated by propionic acid, DMF, and water molecules, contribute significantly to the energetic favorability and stability of β-sitosterol cocrystals. Computational analyses of the crystal structures of β-sitosterol multicomponent forms have been conducted, focusing on various cocrystals with propionic acid. The study extends to a density functional theory (DFT) analysis of weak intermolecular interactions in a newly identified propionate ester of β-sitosterol. The importance of hydrogen bonding and hydrophobic interactions in dictating the solid-state structure of β-sitosterol cocrystals has been energetically evaluated using DFT, with further characterization through QTAIM (Quantum Theory of Atoms in Molecules); NCIPlot (Non-covalent Interaction plot) and MEP (Molecular Electrostatic Potential) surface analyses. Our findings confirm that while hydrogen bonding networks are energetically significant, hydrophobic interactions also play a crucial role in directing the structure of these cocrystals.