AbstractsEngineering

Cocrystals have gained tremendous interest in pharmaceutical development due to their potential to increase bioavailability. Dissolution could be a major determinant for oral bioavailability, however, its mechanism for these cocrystalline materials has not been well recognized. Lacking knowledge of the dissolution mechanism can lead to misinterpretation of in vitro and in vivo behavior. The purpose of this dissertation is to provide a mechanistic understanding of the dissolution behavior of cocrystals to rationalize the selection process and improve in vivo predictions. Cocrystals usually contain components with different physicochemical properties, such as ionization, diffusivity, and micellar solubilization and each of these properties can impact their rates of dissolution. The main focus of this dissertation is to develop mass transport analyses to evaluate the roles of these properties on dissolution under varying solution conditions. The different diffusivities between the cocrystal components led to the development of two different analyses, the surface saturation and interfacial equilibrium models to describe the dissolution process of cocrystals. Better agreement with the experimental data makes the surface saturation model the preferred choice for flux predictions. This dissertation has demonstrated that the dissolution of cocrystals with ionizable components is dictated by the pH at the dissolving solid surface. This interfacial pH is influenced by both the cocrystal properties and solution composition. Depending on solution conditions, both carbamazepine and ketoconazole cocrystals can exhibit higher, equal, or lower dissolution rates compared to their parent drugs. The carbamazepine cocrystals studied here maintain both dissolution advantage and thermodynamic stability because of their diffusivity advantage. The pH dependence of ketoconazole dissolution is mitigated through cocrystallization with acidic coformers. Similar to pharmaceutical salts, cocrystals also exhibit common coformer effect in which the dissolution rates decrease with increasing coformer solution concentration. By incorporating the independently determined values of physicochemical properties of cocrystal components and solution composition into the mass transport analyses, the flux of cocrystals as a function of bulk pH, surfactant, coformer and buffer concentration can be accurately predicted. These mass transport analyses provide the fundamental knowledge of cocrystal dissolution and the opportunity to predict and rationalize the design of cocrystals for optimal oral absorption. Advisors/Committee Members: Amidon, Gregory E (committee member), Rodriguez-Hornedo, Nair (committee member), Chen, Zhan (committee member), Sun, Duxin (committee member).