Aspects of Isostructurality and Polymorphism in a Diverse Group of Monosubstituted Acetanilides

The dependence of crystal structure assembly on molecular changes is studied for a series of monosubstituted acetanilide compounds. A library of 81 crystal structures is obtained from the Cambridge Structural Database, structural similarities are determined, and energetic preferences are assessed. Two dominant amide-amide hydrogen bond geometries and a molecular stack are frequently observed especially in the para-acetanilide subgroup. In all cases, the amide functional group has a greater effect on the chain geometry and resultant crystal packing than the phenyl substituent. The study concludes with a short review of the polymorphism of paracetamol and suggests an alternative concept for overcoming the compaction issues currently encountered in the manufacture of the oral dosage form.