Pharmaceutical solid forms, like salts and cocrystals, play a crucial role in drug formulation. Despite differing mainly by a single hydrogen atom, the regulatory requirements set by the US Food and Drug Administration for these forms vary significantly. We previously developed a DFT-based computational method to distinguish salts from cocrystals. This method, validated on 95 structures, performed well for systems where hydrogen bonds were longer than 2.613 (16) Å. Here, benefits of the rSCAN functional over the PBE functional are discussed. We expand the dataset to 404 cocrystal models. Analysis confirms that 301 of these forms are indeed cocrystals. Additionally, 87 salt-cocrystal continuum forms are identified and 16 cocrystals are classified as possible salts. These 16 problematic structures are further investigated and for seven of them, single crystals were grown and their structure determined using single-crystal X-ray diffraction. Among the phases exhibiting salt-like behaviour, five of them are identified as salts. In some cases, rSCAN alone gives unreliable results for strong hydrogen bonds, but these discrepancies are often corrected using better-renormalized or hybrid functionals (i.e. r2SCAN, PBE0 and PBE50). For future calculations, we recommend using the r2SCAN functional for salt-cocrystal differentiation, as it provides reliable results for O-H...N bonds longer than 2.554 (5) Å. The r2SCAN functional offers a good balance between accuracy and computational efficiency for systems with longer O-H...N bonds.

• Klíčová slova
• DFT-D, cocrystal, cocrystal structures, salt, verification,
• Publikační typ
• časopisecké články MeSH

The binding free energy of hydrogen-bonded complexes is generally inversely proportional to the solvent dielectric constant. This occurs because the solvent-accessible surface area of the complex is always smaller than that of the individual subsystems, leading to a reduction in solvation energy. The present study explores the potential for stabilizing hydrogen-bonded complexes in a solvent with higher polarity. Contrary to the established understanding, we have demonstrated that the hydrogen-bonded complex (CH3CH2COOH⋅⋅⋅2,4,6-trimethylpyridine) can be better stabilized in a solvent with higher polarity. In this case, a significant charge transfer between the subsystems results in an increased dipole moment of the complex, leading to its stabilization in a more polar solvent. The expected inverse relationship between binding free energy and solvent dielectric constant is observed when the charge transfer between the subsystems is low. Thus, the magnitude of the charge transfer between subsystems is possibly the key factor in determining the stabilization or destabilization of H-bonded complexes in different solvents. Here, we present a comprehensive study that combines experimental and theoretical approaches, including nuclear magnetic resonance (NMR), infrared (IR) spectroscopies and quantum chemical calculations to validate the findings.

• Klíčová slova
• Hydrogen bonding, IR, Metadynamics, Micro-solvation, NMR, ONIOM, Solvent effect,
• Publikační typ
• časopisecké články MeSH