The purpose of this work is to increase the efficiency of the cocrystal formation process by thermodynamic modeling using PC-SAFT. By accounting for the thermodynamic non-ideality of the components in the cocrystal system, PC-SAFT is able to model and predict the solubility behavior of pharmaceutical cocrystals based solely on the knowledge of a single cocrystal solubility point in any solvent and at any temperature. Furthermore, the cocrystal solubility in other solvents and for other temperatures can be predicted without the need for additional measurements. The (+)-mandelic acid/(-)-mandelic acid (1:1), caffeine/glutaric acid (1:1) and carbamazepine/nicotinamide (1:1) cocrystal systems were modeled, and the results were in excellent agreement with the experimental data.

The solubility of pharmaceutical cocrystals in aqueous solution is influenced by pH-dependent dissociation and salt formation which complicates the design of cocrystal formation and purification processes. To increase the efficiency of those processes, the aqueous solubility of pharmaceutical cocrystals was predicted in this work using perturbed-chain statistical associating fluid theory (PC-SAFT). Modeling results and experimental data of pH-dependent solubilities were compared for the weak base nicotinamide, the weak acid succinic acid, their 2:1 cocrystal, as well as for all occurring salts at 298.15 and 310.15 K. It was found that the pH-dependent acid–base equilibria of nicotinamide and succinic acid directly influence the solubility of their cocrystal and their salts. By accounting for the thermodynamic nonideality of the components in the cocrystal system, PC-SAFT is able to predict the solubility behavior of all above-mentioned components in good agreement with the experimental data.

Abstract:In this work, the solubilities of pharmaceutical cocrystals in solvent/anti-solvent systems were predicted using PC-SAFT in order to increase the efficiency of cocrystal formation processes. Modeling results and experimental data were compared for the cocrystal system nicotinamide/succinic acid (2:1) in the solvent/anti-solvent mixtures ethanol/water, ethanol/acetonitrile and ethanol/ethyl acetate at 298.15 K and in the ethanol/ethyl acetate mixture also at 310.15 K. The solubility of the investigated cocrystal slightly increased when adding small amounts of anti-solvent to the solvent, but drastically decreased for high anti-solvent amounts. Furthermore, the solubilities of nicotinamide, succinic acid and the cocrystal in the considered solvent/anti-solvent mixtures showed strong deviations from ideal-solution behavior. However, by accounting for the thermodynamic non-ideality of the components, PC-SAFT is able to predict the solubilities in all above-mentioned solvent/anti-solvent systems in good agreement with the experimental data.

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 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 non-ideality 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.

Cocrystal-formation processes from aqueous solutions are often affected by pH-dependent dissociation, polymorphic transitions, as well as by formation of hydrates and salts. To enhance the efficiency of those processes, the aqueous stability and solubility of pharmaceutical cocrystals were predicted in this study using the Perturbed-Chain Statistical Associating Fluid Theory (PC-SAFT). The solubilities in the binary systems caffeine/water and oxalic acid/water were modeled including hydrate formation and polymorphic transitions between the corresponding anhydrate forms I and II. Moreover, pH-dependent solubilities of these hydrate-forming components, their 2:1 cocrystal as well as for all appearing salts were measured and modeled at 298.15 K. It was found, that the pH-dependent acid-base equilibria of caffeine and oxalic acid directly influence the stability and solubility of their cocrystal, their hydrates and salts. In consideration of the thermodynamic non-ideality of the components in the cocrystal system, PC-SAFT enables the solubility predictions of the before-mentioned components as well as if any cocrystal is formed at given conditions of pH and temperature.