Polymorphs, Hydrates, Cocrystals, and Cocrystal Hydrates: Thermodynamic Modeling of Theophylline Systems

Polymorphic transitions and hydrate formation often occur in systems of cocrystal-forming components. To increase the efficiency of cocrystal formation and purification processes, the complex phase behavior of such systems was modeled using perturbed-chain statistical associating fluid theory (PC-SAFT). This is demonstrated for theophylline, a well-studied pharmaceutical, exhibiting polymorphs, as well as formation of a hydrate, cocrystals, and even cocrystal hydrates. The solubility of theophylline in water was modeled including hydrate formation (1:1) as well as polymorphic transitions of theophylline between the anhydrate forms IV, II, and I. The solubilities of theophylline(IV), the thermodynamically stable form at ambient conditions, and the theophylline/glutaric acid (1:1) cocrystal could be predicted without performing additional measurements. Moreover, the complex phase behavior of the theophylline/citric acid/water system could be correlated accounting for the formation of the theophylline hydrate (1:1), citric acid (1:1) hydrate, theophylline/citric cocrystal (1:1), and the corresponding cocrystal hydrate (1:1:1). By accounting for the thermodynamic nonideality of the components in the cocrystal system, PC-SAFT is able to model the solubility behavior of all above-mentioned components in good agreement with the experimental data.