Engineering Cocrystal and Cocrystalline Salt Solubility by Modulation of Solution Phase Chemistry.

Abstract

There is increasing interest in cocrystal and cocrystalline salts as alternate pharmaceutical solid forms because they provide a range of physicochemical and biopharmaceutical properties. Both cocrystals and cocrystalline salts provide an opportunity to alter not only the lattice chemistry but also the solution chemistry of the parent drug. There are numerous reports of cocrystals and cocrystalline salts that enhance the aqueous solubility and in some cases bioavailability of hydrophobic drugs. The most common method used to characterize the solution behavior of these solid forms is currently powder dissolution. This approach may not identify rapidly transforming metastable cocrystals and cannot be extrapolated to other solution conditions. Cocrystal forms are often evaluated in the presence of additives that affect the solution chemistry of the cocrystal components thereby impacting cocrystal solubility and thermodynamic stability. This dissertation explores the influence of solution chemistry on cocrystal and cocrystalline salt solubility and thermodynamic stability relative to the parent drug and salt respectively. Knowledge of the solution mechanisms that alter the cocrystal component solubilities can be used to anticipate cocrystal solubility and Scocrystal/Sdrug. The objectives of this work are to (1) to determined the key thermodynamic parameters necessary to rationally select surfactants to modulate cocrystal solubility and Scocrystal/Sdrug using mathematical models derived from knowledge of the solution-chemistry affecting the cocrystal components (2) to evaluate the contributions of ionization and micellar solubilization to cocrystal solubility and Scocrystal/Sdrug in physiologically relevant media (3) to derive mathematical models that describe cocrystalline salt solubility dependence on ionization and the common-ion effect so that the solubility of these solid forms can be characterized using minimal experimental measurements (4) to develop a method to characterize the equilibrium solubility of metastable cocrystalline salts and (5) to examine the relationship between the relative magnitude of Scocrystal/Sdrug and the observed supersaturation relative to the parent drug.