Engineering cocrystal solubility and stability via ionization and micellar solubilization.

Abstract

Pharmaceutical cocrystals have generated enormous interest due to their potential for improving the physicochemical shortcomings of a drug, such as poor aqueous solubility. Poor aqueous solubility can compromise drug performance and cocrystallization is an emerging strategy to design materials with desirable properties. This approach is currently limited because cocrystal solution chemistry remains largely unexplored. This dissertation explores the influence of two critically important solution phase interactions, ionization and micellar solubilization, on cocrystal solubility and stability. The objectives of this work are to (1) understand the effect of ionization on cocrystal solubility, (2) investigate the role of micellar solubilization on cocrystal solubility and stability, (3) develop mathematical models to describe cocrystal solubility and stability via ionization and micellar solubilization equilibria, and (4) understand how ionization and micellar solubilization affect cocrystal eutectic points and regions of thermodynamic stability. Cocrystal solubility, stability, and eutectic points were investigated as a function of pH and sodium lauryl sulfate concentration for a series of carbamazepine cocrystals in water. The cocrystals represented two stoichiometries (1:1 and 2:1) and four coformers (salicylic acid, saccharin, 4-aminobenzoic acid, and succinic acid) with various ionization properties. Mathematical models for cocrystal solubility were developed in terms of experimentally accessible thermodynamic parameters based on cocrystal dissociation, component ionization, and micellar solubilization. These models demonstrated that cocrystal solubility relative to drug could be strongly dependent on surfactant concentration and pH, and that the thermodynamic stability of cocrystals could be controlled via predictable parameters called the critical stabilization concentration (CSC) and pHmax. This enabled for the first time the thermodynamic stabilization of cocrystals that would otherwise be unstable in water under stoichiometric solution conditions. Several methods were developed to evaluate CSC and were challenged by the carbamazepine cocrystals. The important factors that affect CSC and pHmax were identified as (1) cocrystal aqueous solubility relative to drug, (2) micellar solubilization constants and acid dissociation constants for the cocrystal components, (3) cocrystal stoichiometry, and (4) surfactant CMC. The mathematical models demonstrated excellent predictive capacity in describing the influence of pH and surfactant concentration on cocrystal solubility, CSC, and eutectic points for the carbamazepine cocrystals.