Coarse-Grained Drug Molecule Simulation and Polymorph Discovery

We describe a coarse-graining method used to study crystallization and polymor- phism in a pharmaceutically relevant drug molecule, all via computer simulation. Our coarse-grained model is capable of capturing the stability of the experimentally- known orthorhombic crystal (space group Pna21), the crystal lattice parameters, and the preferred growth direction (the [100] direction) from the melt. By applying meta-dynamics to the coarse-grained model, a new crystalline form of the drug was discovered (monoclinic, space group P21), which contains two molecules per unit cell. Atomistic simulations and quantum calculations then showed the polymorph to be meta-stable at ambient temperature and pressure, as well as thermodynamically more stable than the conventional orthorhombic crystal at high pressure. The strategy described in this study could be an efficient route to polymorph prediction in other types of small molecules.