Crystal structures of racemic and homochiral forms of 2-phenylbutyramide (1) and 3-methyl-3-phenylpyrrolidine-2,5-dione (2) were investigated in detail by a single crystal X-ray diffraction study. Absolute configurations of the homochiral forms of 1 and 2, obtained by chromatographic separation of racemates, were determined. It was revealed that racemate and homochiral forms of 1 are very similar in terms of supramolecular organization (H-bonded ribbons) in crystal, infrared (IR) spectral characteristics, and melting points. The presence of two different molecular conformations in homochiral forms of 1 allowed mimicking of crystal packing of the H-bonded ribbons in racemate 1. Two polymorph modifications (monoclinic and orthorhombic) comprising very similar H-bonded zigzag-like chains were found for the homochiral forms of compound 2 that were significantly different in terms of crystal structure, IR spectra, and melting points from the racemic form of 2. Unlike compound 1, homochiral forms of compound 2 have a higher density than the corresponding racemate which contradicts the Wallach rule and indicates that, in this case, homochiral forms are more stable than racemate forms.

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.