In this work, we propose the XO-PBC method, which combines the eXtended ONIOM method (XO) with the periodic boundary condition (PBC) for the description of molecular crystals. XO-PBC tries to embed a finite cluster cut out from the solid into the periodic environment, making it feasible to employ advanced molecular quantum chemistry methods, which are usually prohibitively expensive for direct PBC calculations. In particular, XO-PBC utilizes the results from force calculations to design the scheme to fragment the molecule when crystals are made of large molecules and to select cluster model systems automatically consisting of dimer up to tetramer interactions for embedding. By applying an appropriate theory to each model, a satisfactory accuracy for the system under study is ensured, while a high efficiency is achieved with massively parallel computing by distributing model systems onto different processors. A comparison of the XO-PBC calculations with the conventional direct PBC calculations at the B3LYP level demonstrates its accuracy at substantially low cost for the description of molecular crystals. The usefulness of the XO-PBC method is further exemplified, showing that XO-PBC is able to predict the lattice energies of various types of molecular crystals within chemical accuracy (<4 kJ/mol) when the doubly hybrid density functional XYG3 is used as the target high level and the periodic PBE as the basic low level. The XO-PBC method provides a general protocol that brings the great predictive power of advanced electronic structure methods from molecular systems to the extended solids.

Polymorph discrimination for a molecular crystal has long been a challenging task, which, nonetheless, is a major concern in the pharmaceutical industry. In this work, we have investigated polymorph discrimination on three different molecular crystals, tetrolic acid, oxalic acid, and oxalyl dihydrazide, covering both packing polymorphism and conformational polymorphism. To gain more understanding, we have performed energy decomposition analysis based on many-body expansion, and have compared the results from the XO-PBC method, that is, the eXtended ONIOM method (XO) with the periodic boundary condition (PBC), with those from some commonly used dispersion corrected density functional theory (DFT-D) methods. It is shown here that, with the XYG3 doubly hybrid functional chosen as the target high level to capture the intra-and short-range intermolecular interactions, and the periodic PBE as the basic low level to take long range interactions into account, the XO-PBC (XYG3:PBE) method not only obtains the correct experimental stability orderings, but also predicts reasonable polymorph energy ranges for all three cases. Our results have demonstrated the usefulness of the present theoretical methods, in particular XO-PBC, while highlighted the importance of a better treatment of different kinds of interactions to be beneficial to polymorph control.