Thermodynamics and Crystallization of the Theophylline–Glutaric Acid Cocrystal

Abstract

This work investigates the thermodynamics and crystallization of the theophylline–glutaric acid 1:1 cocrystal. It is found that the cocrystal physically decomposes at 120 °C (i.e., in the range between the melting points of the two pure compounds). The solubility of the cocrystal and pure compounds has been determined in chloroform and acetonitrile. In chloroform, the theophylline concentration of the saturated solution over the cocrystal is clearly higher than that in the saturated solution over pure theophylline I/II, while for glutaric acid the situation is the opposite. With the solubility data, the Gibbs free energy of the formation of the cocrystal from solid theophylline II and solid β-glutaric acid at 30 °C can be estimated to −0.39 kJ mol–1. The work reveals that polymorphism in the pure components of a cocrystal can dramatically influence the phase diagram and shift an incongruently dissolving case into a kinetically stabilized congruent case. In chloroform, the cocrystal dissolves incongruently...