Conformational polymorphs, multiple Z′ crystal structures and phase transformations

Abstract

Molecular conformer (Econf) and crystal lattice energy (U latt) contributions are of comparable magnitude in crystal structures of flexible molecules. Bond torsion variations about C-C single bonds are worth 1-3 kcal mol-1 and hydrogen bonds, intermolecular interactions have energy of 1-10 kcal mol-1. Both these energy factors should be considered in calculating the total crystal energy (Etotal) of organic crystalline solids. Intra- and intermolecular contributions may be additive or cancel one another. Polymorphism is likely in molecular systems wherein molecular conformer and crystal energy effects compensate one other, i.e. a metastable conformer resides in a stable packing arrangement or a stable rotamer is present in a metastable crystal environment. Organic conformational polymorphs are found to be promiscuous in a small energy window of < 3 kcal mol-1. Polymorph clusters having different number of symmetry-independent molecules in the unit cell are discussed and their phase transformations monitored by variable temperature powder X-ray diffraction and differential scanning calorimetry. The final section deals with polymorphism in pharmaceuticals and the need to know the most stable polymorph of drug molecules.