Thermodynamics and Crystallization of the Theophylline-Glutaric Acid Cocrystal

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 degrees 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 beta-glutaric acid at 30 degrees 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 with respect to the stable form I of theophylline but congruently with respect to the metastable theophylline II. However, the cocrystal is stable in a stoichiometric solution for more than 2 weeks. Given sufficient time, the system should transform into a solid phase being a mixture of cocrystal and stable theophylline I, in equilibrium with a solution that has the composition of the corresponding invariant point. In acetonitrile, where the glutaric acid solubility is much higher than that of theophylline II, the cocrystal dissolves, clearly incongruently. The region where the cocrystal is the only solid stable phase is clearly shifted toward the glutaric acid side and is fairly narrow. In both solvents the cocrystal can readily be produced by isothermal slurry conversion crystallization to a reasonable level of productivity, as long as the process is operated in a region of the phase diagram where the cocrystal is the only stable (or reasonably metastable) solid phase.