Origin of the Thermodynamic Stability of the Polymorph IV of Crystalline Barbituric Acid: Evidence from Solid-State NMR and Electron Density Analyses Zahra Badri, † Kater ̌ ina Bouzkova ́ , † Cina Foroutan-Nejad, ‡ and Radek Marek* ,†,‡,§ † CEITEC - Central European Institute of Technology, ‡ National Center for Biomolecular Research, and § Department of Chemistry, Faculty of Science, Masaryk University, Kamenice 5/A4, CZ-62500 Brno, Czech Republic * S Supporting Information ABSTRACT: In this contribution, the origin of the stability of the polymorph IV (enol form) of crystalline barbituric acid relative to the polymorph II (keto form) is investigated using solid-state NMR spectroscopy and electron density analysis. Electron density analysis reveals differences in the nature of the intermolecular contacts in the different polymorphs of barbituric acid. Comparing the properties of hypothetical single molecules of barbituric acid with cluster models shows that the electronic and magnetic properties of polymorphs of barbituric acid can be employed to measure the strengths of the intermolecular interactions. Changes in the magnitudes of the NMR chemical shift tensors are also shown to be parallel to the intermolecular delocalization index of Quantum Theory of Atoms in Molecules, which measures the covalency of an intermolecular interaction. 1. INTRODUCTION Polymorphism, the ability of a chemical substance to form more than one crystalline form in the solid state, is well-known in chemistry. It has been identified among different classes of compounds and for chemical elements, where it is known as allotropy. It is also found in biologically active materials. Polymorphism plays an important role in the pharmaceutical industry because it has frequently been observed that only one of several crystalline forms of a drug is sufficiently active to be useful. 1 Among pharmaceutical molecules, polymorphism usually occurs as a result of di ffering intermolecular interactions 2,3 between individual molecules in the solid state. 4,5 The characterization of crystal structure based on intermolecular interactions is therefore crucial to observing the generation of different polymorphs. 6 Different crystal forms of a molecule differ in properties such as stability, solubility, and bioavailability. 7 A recent study on barbituric acid 8 revealed that at ambient conditions the most thermodynamically stable form is polymorph IV (formed by the enol tautomer), 9 whereas polymorph II, which is the commercially available form (formed by the keto tautomer depicted in textbooks), is relatively unstable (Scheme 1). However, it has been demonstrated that the keto form is generated in other conditions. 10-14 These two forms of barbituric acid are trapped in specific networks of intermolecular contacts, such as hydrogen bonding (H-bonding) or π···π stacking. Theoretical calculations indicate that the intermolecular interactions in the crystal environment should favor the enol form over the keto form by 58.5 kJ·mol -1 , whereas gas-phase studies suggest that the molecule in its keto tautomer is 53.7 kJ · mol -1 lower in energy. 8 Indeed, intermolecular interactions reverse the order of thermodynamic stability of the tautomers, favoring the enol form in the solid state and the keto tautomer in the gas phase and in solution. It has been demonstrated that the crystal of polymorph II consists of two different conformers of keto tautomer: 9 an envelope conformation and a planar conformation (see Figure 1). In the envelope conformer, K1, the hydrogen atoms bonded to carbon atom C5 are oriented pseudo axial and pseudo equatorial with respect to the six-membered ring. In the planar conformer, K2, both hydrogen atoms of C5 assume similar angles to the plane of the molecule resulting in an Received: December 19, 2013 Revised: May 6, 2014 Published: May 7, 2014 Scheme 1. Keto (K) and Enol (E) Tautomeric Forms of Barbituric Acid Article pubs.acs.org/crystal © 2014 American Chemical Society 2763 dx.doi.org/10.1021/cg401899q | Cryst. Growth Des. 2014, 14, 2763-2772