Characterization, Analysis, and Theoretical Calculation Studies of Solvates and Cocrystals of Betulin: An Exploration of the Boundary between Solvates and Cocrystals

Cocrystals, as an excellent solid state to improve the physicochemical properties of active pharmaceutical ingredients, have always been discussed together with solvates since the definition of cocrystals was proposed. However, investigation and discussion of the boundary between cocrystals and solvates have not been common. In this work, aiming at betulin (BE), a natural product with multiple pharmacological activities, we designed its polymorphism and cocrystal screening experiments with different liquid organic solvents and solid cocrystal coformers (CCFs) that possess low and high melting points, respectively. Afterward, a hemihydrate, a new solvate with benzyl alcohol, and two new cocrystals of BE with phenol (PHE) and 3-hydroxybenzoic acid (3-HBA), respectively, including their single crystal structures, were designed, prepared, and characterized by single-crystal X-ray diffraction, powder X-ray diffraction, and other solid-state analysis methods. A special thermal property for pharmaceutical cocrystals was found in cocrystal BE–PHE, that is, it possesses an exact CCF loss process, which is different from cocrystal BE–3-HBA but is similar to the solvate of BE. To explain this phenomenon, theoretical calculation studies were performed by molecular electrostatic potential surface analysis, electron density difference analysis, energy decomposition analysis, and energy framework analysis to realize an in-depth study of the sites, quantities, and energy of the intermolecular interactions between BE and different coformer molecules. Results indicated that the fewer interaction sites and the small interaction energy between BE and PHE molecules are possible reasons for the unusual thermal properties of cocrystal BE–PHE. This finding also proved that the structural features of cocrystals can greatly affect their physicochemical properties.