Pharmaceutical Cocrystal Eutectic Analysis: Study of Thermodynamic Stability, Solubility, and Phase Behavior

Abstract

Cocrystals are an emerging solid-state form to change physicochemical and biopharmaceutical drug properties. This dissertation focuses on the thermodynamic stability and solubility of pharmaceutical cocrystals. Specifically, the objectives are to: (i) develop methods to measure the thermodynamic solubility of metastable cocrystals, (ii) provide models that describe the equilibrium phase behavior of cocrystals based on component and cocrystal properties, (iii) explain the effect of temperature on cocrystal thermodynamic stability, (iv) estimate solubility and stability for different solvents based on component activity coefficients and measured cocrystal solubility in one solvent, and (v) identify mechanisms by which hygroscopic additives affect the stability of mixtures of solid cocrystal components. Cocrystal solubilities were calculated from eutectic concentration measurements where solution is in equilibrium with solid drug and cocrystal. Cocrystal solubility was directly proportional to coformer eutectic concentration and to the solubility of cocrystal components for carbamazepine, caffeine, and theophylline cocrystals. Cocrystal eutectic constants (Keu), the ratio of solution activities of cocrystal components at the eutectic, are fundamental indicators of phase behavior and are a function of the cocrystal to drug solubility ratio (α) in pure solvent. More than forty eutectic constants are presented that demonstrate Keu dependence on i) solvent, ii) complexation, and iii) ionization, as does the solubility of cocrystals. Applications of these findings to the discovery and phase stability of carbamazepine-sarcosine anhydride cocrystals are presented. A solution-mediated mechanism of cocrystal formation is shown for cocrystal components mixed with hygroscopic additives that sorbed moisture. More cocrystal formation occurred for additives that lowered the Keu. Keu temperature dependence is explained by thermodynamic models based on cocrystal and component enthalpies of solution, which are solvent specific. The Keu and α values of carbamazepine-nicotinamide in water decreased with temperature, but for several organic solvents Keu was temperature independent (4-47˚C). Cocrystal solubility and stability was also shown to depend on the component activity coefficients, which were estimated using the component solubilities. The models developed based on component and cocrystal properties combined with methods to estimate cocrystal solubilities from eutectic concentrations provide a useful guide for cocrystal design, synthesis, and selection.