pubs.acs.org/crystal Published on Web 06/01/2010 r 2010 American Chemical Society DOI: 10.1021/cg100457r 2010, Vol. 10 3306–3310 Charge Density Analysis of Crystals of Nicotinamide with Salicylic Acid and Oxalic Acid: An Insight into the Salt to Cocrystal Continuum Venkatesha R. Hathwar, Rumpa Pal, and T. N. Guru Row* Solid State and Structural Chemistry Unit, Indian Institute of Science, Bangalore-560012, Karnataka, India Received April 6, 2010; Revised Manuscript Received May 15, 2010 ABSTRACT: Charge density analysis from both experimental and theoretical points of view on two molecular complexes: one is formed between nicotinamide and salicylic acid, and the other formed between nicotinamide and oxalic acid brings out the quantitative topological features to distinguish a cocrystal from a salt. One of the recent developments in the pharmaceutical industry is to enhance the physical properties of active pharmaceutical ingredients (APIs) by forming “cocrystals”. 1 Most of the APIs are administered in the solid form, and it is desirable to extract the maximum benefits of their potency. Even though a proper definition for a cocrystal is not available, it is generally under- stood that a cocrystal is a multicomponent solid form made of neutral molecules. On the other hand, a salt is made of any pair of ionized molecules. 1-3 Indeed, a formal definition for the forma- tion of a cocrystal was given by Dunitz, 4 in a reply to the comment made by Desiraju; 5 however, this definition includes hydrates, solvates, as well as solid solutions of molecular complexes. In an effort to investigate the salt to cocrystal continuum in terms of ΔpK a (pK a of base - pK a of acid) value rule, 2d it has been observed that a crystal engineering approach focused on the selection of the counterions for an ionizable API based on intermolecular interaction is more appropriate instead of pK a values alone. 6 In particular, the dependence on ΔpK a value ranging between 0 and 3 does not ensure a salt formation in the solid state. This dependence on ΔpK a values is validated based on the study containing theophylline and 20 other coformers with ΔpK a <0. 2d However, it must be borne in mind that these ΔpK a values are not directly transferable to the crystalline state. The pH dependence studies to control cocrystal formation using hydrogen bonds in γ-amino butyric acid 7 have demonstrated the overlap of the salt to cocrystal continuum. Mechanochemical cocrystallization which involves grinding the coformers, which has been recently reviewed, 8 provides the best possible approach to obtain cocrystals. Utilization of techniques such as X-ray photoelectron spectroscopy (XPS), solid state NMR (ssNMR), and FTIR together provide information on the location of protons and hence allow for identification of a cocrystal from a salt. 9 In recent years, charge density analysis based on experimental and theoretical calculations has reached a stage where topological features allow for obtaining net atomic charges and related one- electron properties, leading to the derivation of features related to chemical bonding directly. 10 The use of the “quantum theory of atoms in molecules” (QTAIM) 11 approach provides a quantitative link between total electron density and the physical properties of a molecule. It is to be pointed out that the treatment of electron density associated with hydrogen atoms is critical. 12-14 The nature of bonding in both intra- and intermolecular regions can be evaluated in terms of the deformation density 15 obtained using the multipolar refinement based on the Hansen-Coppens model. 16 Computation of charge densities from theory without any depen- dence on experimental values involves the well-established methods of computing molecular orbitals using either Hartree-Fock (HF) or density functional theory (DFT). CRYSTAL06 17 allows for such calculations including the periodicity in the crystal lattice. In this article, we have analyzed the charge density distribu- tion of two molecular complexes, a cocrystal formed by nicotin- amide and salicylic acid and a salt formed by nicotinamide and oxalic acid (Scheme 1). 18 We have considered nicotinamide to represent API and two acids, namely oxalic acid and salicylic acid, as salt and cocrystal formers based on their pK a values. The nicotinamide ring is the reactive part of nicotinamide adenine dinucleotide (NAD), which along with its corresponding phosphate (NADP) forms the basis for many biological oxidation-reduction reactions. 19 Since the pK a value of oxalic acid is 1.23 and that of salicylic acid is 2.97, it was anticipated that the ΔpK a value of nicotinamide (pK a =3.35) and oxalic acid would be sufficiently large to ensure salt formation whereas the corresponding value for salicylic acid would suggest cocrystal formation. 2d Figure 1 shows the ORTEP 20 diagram of nicotinamide with the coformers salicylic acid and oxalic acid, respectively. Hydrogen atoms (highlighted in Figure 1) were uniquely located in both cases using SHELX. 21 In nicotinamide, the nitrogen atom at the pyridine group can form heterosynthons resulting in an acid-pyridine, an amide- pyridine, or a hydroxyl-pyridine hydrogen bonded motif. It can also form homosynthons with the involvement of amide-amide or pyridine-pyridine moieties. 22 The packing of the molecules in both the crystals studied in this article shows significant differ- ences in synthon formation (Figure 2). A heterosynthon is preferred in the cocrystal (acid-pyridine) while a homosynthon is observed in the salt (amide-amide). Further, a N-H 333 O Scheme 1. Schematic Diagram of a Cocrystal and a Salt between the Two Independent Coformers a a The dotted line indicates hydrogen bond formation between the acceptor and the donor atom. *E-mail: ssctng@sscu.iisc.ernet.in.