DOI: 10.1021/cg100457r
Charge Density Analysis of Crystals of Nicotinamide with Salicylic Acid and Oxalic Acid: An Insight into the Salt to Cocrystal Continuum
2010, Vol. 10 3306–3310
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 understood 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 formation 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 ΔpKa (pKa of base - pKa 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 pKa values alone.6 In particular, the dependence on ΔpKa value ranging between 0 and 3 does not ensure a salt formation in the solid state. This dependence on ΔpKa values is validated based on the study containing theophylline and 20 other coformers with ΔpKa
