A Combination of Virtual and Experimental Screening Tools for the Prediction of Nitrofurantoin Multicomponent Crystals with Pyridine Derivatives

Thirty-four binary systems of nitrofurantoin with pyridine derivatives were analyzed by combining virtual (molecular complementarity prediction and hydrogen bond propensity calculations) and experimental (liquid-assisted grinding) screening methods. A new modification of the hydrogen bond propensity calculation method (the integrated hydrogen bond propensity calculation method) with significantly improved virtual screening efficiency was proposed. Novel cocrystals of nitrofurantoin with 3-aminopyridine and 2-(1H-Imidazol-2-yl)pyridine were discovered. The crystal structures of the new cocrystals were determined from single-crystal X-ray diffraction data, and the hydrogen bond patterns were studied in conjunction with the Molecular Electrostatic Potential maps of the components. The nitrofurantoin cocrystal with 3-aminopyridine was found to exist in two polymorphic modifications. The origins of the different stability of the polymorphic forms were rationalized both in terms of total lattice enthalpy and free energy derived from periodic DFT-D3 calculations and in terms of the non-covalent interaction energy distribution in crystal.

Automated summary

Thirty-four binary systems of nitrofurantoin with pyridine derivatives were studied using virtual and experimental screening methods. A new calculation method for hydrogen bond propensity was proposed, leading to the discovery of novel cocrystals. The crystal structures were determined and analyzed to understand the stability and interactions in the polymorphic forms.