(219b) Characterizing Acid-Base Organic Crystals By Computationally Efficient Periodic System Calculations

The definitive characterization of pharmaceutical salt and cocrystal solid forms is crucial from regulatory and IP perspectives. However, the assignment of acid-base configurations along the salt-cocrystal spectrum solely by single-crystal X-ray diffraction (scXRD) experiments may be ambiguous due to the low scattering power of polar hydrogens. Therefore, additional experimental or theoretical studies may be required to confirm the proton location between acid and base. We benchmarked the applicability and limitations of commonly used computationally efficient periodic system calculations for the characterization of acid-base systems against a dataset of 19 crystals with proton positions experimentally assigned using ssNMR or single-crystal neutron diffraction methods. A practical computational workflow to support the characterization of pharmaceutical acid-base crystals in conjunction with routine scXRD measurements was proposed.