Chasing the Co-crystal Disappearing Polymorph with Ab Initio Methods

Crystal polymorphism has a major impact on material properties such as thermal stability, bioavailability, and solubility. The application of co-crystals in the pharmaceutical industry requires polymorph screening to avoid unwanted phase transitions, which can cause property reduction. In this work, three polymorphs of urea-barbituric acid (1:1) co-crystals were investigated to describe the dynamic character of their H-bond networks and to explain the disappearance of the polar polymorph. For the studied polymorphs, Born-Oppenheimer molecular dynamics simulations were performed. Detailed analysis of hydrogen bonds and power spectra calculations were conducted using the obtained trajectories. The relative stability of each polymorph has been considered in terms of NVT and NVE ensembles. The results of computations were discussed in light of the analysis of H-bond propensities, coordination scores, and the obtained experimental data. To our knowledge, the polar form of urea-barbituric acid co-crystal can be called one of the first known examples of co-crystal disappearing polymorph.