Thermodynamic and Kinetic Parameters that Explain Crystallization and Solubility of Pharmaceutical Cocyrstals.

Abstract

Cocrystals have emerged as a viable alternative to increase the diversity of solid-state drug forms. Literature surrounding cocrystals range from design using crystal engineering principles to evaluating the pharmaceutical properties of cocrystals. This dissertation focuses on understanding thermodynamic and kinetic parameters that explain cocrystal crystallization and solubility. This thesis will address the following key questions concerning pharmaceutical cocrystals (1) do cocrystals offer any advantages over other solid-state forms, (2) what are the criteria for cocrystal former selection, (3) can cocrystal screening and crystallization methods be theoretically based, and (4) can pH-dependent solubility be imparted to non-ionizable drugs by cocrystallizing them with ionizable co-formers? Mathematical models developed throughout this thesis describe cocrystal solubility dependence on dissociation, solution complexation, and ionization. Carbamazepine-nicotinamide and carbamazepine-saccharin solubility dependence on nicotinamide or saccharin concentration follows solubility product behavior. Cocrystal solubility decreases with increasing coformer concentration. Models developed were used to generate phase solubility diagrams (PSD) that show cocrystal and drug stability domains. Based on the PSD, a theoretically based reaction crystallization method for high-throughput cocrystal screening and scalable cocrystal synthesis is developed. As aqueous solubility is critical for every pharmaceutical compound, pH-dependent solubility and dissolution were studied since many of the cocrystal components are ionizable. Theoretical models are developed that rationalize and predict cocrystal solubility and stability dependence on pH and component pKa for cocrystals of different stoichiometries and ionization properties. Studies with carbamazepine-saccharin, carbamazepine-salicylic acid, and carbamazepine-4-aminobenzoic acid show that cocrystals can impart pH-dependent solubility and dissolution to a non-ionizable drug when cocrystallized with ionizable coformers. Because carbamazepine cocrystal solubility was higher than carbamazepine dihydrate solubility, the cocrystal solubility in solvent without excess cocrystal component was calculated by measuring the transition concentration dependence on pH. However, gabapentin-3-hydroxybenzoic acid cocrystal solubility was measured in pure solvent over a pH range in which the solubility of the cocrystal was lower than gabapentin hydrate. The theoretical models presented delineate the crystal and cocrystal stability domains with a minimum number of experiments and predict cocrystal solubilities that are experimentally inaccessible.