Co-Crystal Polymorphs from a Solvent-Mediated Transformation

Abstract

co-crystals of carbamazepine and isonicotinamide can form through a solvent-mediated transformation process when a dry mixture of the pure crystalline components is suspended in ethanol. First, needle-like crystals (form II) grow while the pure crystalline components dissolve. Eventually plate-like crystals (form I) grow at the expense of the needle-like crystals. Single crystal structure determination showed that form I consists of chains of alternating dimers of carbamazepine and dimers of isonicotinamide. The powder diffraction pattern and the needle-like shape of form II show that it most probably is isostructural to the known 1:1 co-crystal structure of carbamazepine and nicotinamide, consisting of dimers of carbamazepine linked to chains of nicotinamide through hydrogen bonding. In both form I and form II, the pyridine heteronitrogen of isonicotinamide does not participate in hydrogen bonding. Both co-crystal structures have 1:1 stoichiometry, and they are therefore polymorphs. The solvent-mediated transformation showed that form I is the stable form at room temperature. The phase diagram for carbamazepine-isonicotinamide in ethanol shows that an excess of isonicotinamide is optimum to form co-crystals, and that solutions with 1:1 stoichiometry result in carbamazepine crystals or at best mixtures of carbamazepine and co-crystals. Under optimal conditions, determined by the pure component solubilities, the solvent-mediated transformation method is a simple and effective way of searching for co-crystal polymorphs.