A Study On Thermodynamic Phase Diagrams And Solution Behavior Of Pharmaceutical Cocrystal

Pharmaceutical cocrystals viewed as an addition to the existing class of pharmaceutical crystalline solids can improve the physicochemical and biopharmaceutical properties of drugs without changing their chemical structure. The development of pharmaceutical cocrystals might offer advantages over the active pharmaceutical ingredients(APIs) and may overcome some of the limitations encountered with classical strategy(polymorph, solvate and salt formation). In recent years, cocrystals have recently gained much attention for pharmaceutical development especially because it has great advantages in improving the solubility and dissolution rates of API. Knowledge of thermodynamics of the cocrystal in crystallization is important for efficient cocrystal screening and scale-up, and aqueous solubility is an important parameter in drug development. The aim of the study in this thesis was to investigate the thermodynamics knowledge and solubility behavior in aqueous medium of 1:1 IBU-NCT cocrystal, CBZ-NCT cocrystal and IMC-NCT cocrystal.IBU-NCT cocrystal, CBZ-NCT cocrystal and IMC-NCT cocrystal were prepared by solvent-assistant co-grinding and cooling cocrystallization from solution, and were charactered by a variety of methods. Ternary phase diagrams for the three cocrystals in both pure solvent and solvent mixtures were constructed using static equilibrium method. Safe operation regions were determined from the phase diagrams. As for the encountered asymmetric diagrams and competition of cocrystal formation with solvate formation, a new strategy was proposed — cocrystal formation from solvent mixtures.Solution chemistry of these cocrystal systems was investigated by considering the solubility product and solution complexation of cocrystal components. Experimental results for the solubility of cocrystal were analyzed in terms of the derived mathematical models. Solubility products and complexation constants were also determined. The solubility of cocrystals were expressed as a function of co-former(NCT) concentration in solution.To understand the dissolution processes of these cocrystals in aqueous medium, the solubility profiles of cocrystals were measured, and [drug concentration] versus [dissolution time] plots were determined(dissolution rates). Cocrystals exhibited dramatic solubility advantage over the stable crystalline drug form. The “spring and parachute” concept for amorphous drug dissolution was adapted to explain the solubility advantage of pharmaceutical cocrystals and phase transformations these drugs underwent during dissolution. A number of possible mechanisms of co-former influence on drug precipitation kinetics were inferred from the theory of drug precipitation. The enhanced solubility of drug cocrystals was similar to the amorphous drugs. However, in contrast to the metastable nature of amorphous phases, cocrystals were stable owing to their crystalline nature.These findings have practical applications in the development of crystallization methods for cocrystal screening and scale-up.