Synthesis Characterization Molecular Modeling of a Pharmaceutical Co-Crystal: (2-Chloro-4-Nitrobenzoic Acid):(Nicotinamide)

ABSTRACTThe active pharmaceutical ingredient 2-chloro-4-nitrobenzoic acid (2c4n) is a potentially novel therapy for immunodeficiency diseases as an anti-viral and anti-cancer agent, and exists as a dimorph in the solid state. The Kofler hot stage contact method was employed to investigate the potential of preparing a co-crystal with nicotinamide (nic), a GRAS compound. The 1:1 co-crystal 1 was made using liquid-assisted grinding and solution crystallization experiments. The crystal structure determination of 1 reveals that the two molecules are associated via a carboxylic acid-pyridine hydrogen bond, while the nic forms a centrosymmetric R22(8) dimer to ultimately form a ribbon architecture which is compared to other known cocrystals of nic. The melting point of the co-crystal is higher than the melting points of either of the pure components, indicating that the pharmaceutical co-crystal is thermally more stable than the pure pharmaceutical compound. The relative stability of the interactions in the co-crystal over the pure compounds is further supported by molecular modeling calculations. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:4054-4071, 2010