Pharmaceutical co-crystals with isonicotinamide – vitamin B3, clofibric acid, and diclofenac – and two isonicotinamide hydrates

Abstract

The co-crystals of three industrially important pharmaceuticalmolecules, the Vitamin B group member nicotinamide (1), the antihyperlipidemic drug clofibric acid (2), and the nonsteroidal anti-inflammatory drug diclofenac (3), are synthesizedwith the co-crystal former isonicotinamide and characterized by thermal analysis and single crystalX-ray diffraction. Two dimorphic hydrates of isonicotinamide were obtained during the course of these experiments: hydrate 4 (formI) has been reported recently, and hydrate 5 (form II) is new. Both are monohydrates but differ in the number of independent molecules in the asymmetric unit, Z0=2 and 8, respectively. Form II is metastable compared to I and converts to form I in the solid state. In all three pharmaceutical co-crystals, it is the pyridine N atom of either the nicotinamide molecule in 1 or the N atom of the isonicotinamide molecule in 2 and 3 that is used in connecting the differentmolecules together, as a hydrogen bond acceptor from the amine of the isonicotinamide in 1 and the carboxylic acid protons in 2 and 3. The carboxylic acid 3 3 3 pyridine hydrogen bond is an often used supramolecular synthon.Asurvey of relevant structures in the Cambridge Structural Database of isonicotinamide and nicotinamide co-crystals is given for completeness, and the co-crystal former ability of isonicotinamide and nicotinamide was investigated by performing density functional theory calculations.