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Molecular arrangements in crystals of racemic and enantiopure forms of N-carbamoyl-2-phenylbutyramide and 2-phenylbutyramide: differences and similarities

Abstract As solid drugs may be regarded as “pharmaceutical materials”, molecular pharmaceutics of such drugs is expected to benefit from application of materials science concepts. In this paper, we used a structural chemistry approach to explain the dramatic difference in solubility between two structurally related antiepileptic drugs, N-carbamoyl-2-phenylbutyramide (NC2PBA) and 2-phenylbutyramide (2PBA). Since both of these compounds are chiral, we chromatographically separated the enantiomers and examined them along with the racemic forms. A combination of experimental (single-crystal X-ray diffraction, IR spectroscopy) and computational (crystal lattice energy calculations, Hirshfeld surface analysis) techniques was employed to determine the structural differences between these two compounds in the crystalline state. We found that while NC2PBA and 2PBA have similar molecular packing arrangements, the former compound is distinguished by a more extensive network of hydrogen bonds. Thus, the higher density, higher melting point, and lower solubility of crystalline NC2PBA compared to crystalline 2PBA may be largely explained by the differences in hydrogen bonding. We also found that for each of these compounds there are no major differences in molecular packing (and, correspondingly, in crystal lattice energies) between racemic and enantiopure forms.