The Thermodynamics And The Solution Complexation Mechanism Of Carbamazepine-Succinic Acid Cocrystal

Pharmaceutical cocrystals can improve the physical and chemical properties without compromising the structural integrity of the active pharmaceutical ingredient (API). It provide an alternative to chemical modification and bioavailability improvement of APIs as well as established salt, amorphous, solvate, and polymorphic drug forms that all have limitations in their utility. The cocrystal research is an exciting scientific subject and is one of the most important compositions for the pharmacy design, pharmacy exploitation and pharmacy production.Carbamazepine (CBZ) is a BCS classⅡcompounds which has low solubility and high permeability. It can form a lot of cocrystals with other coformer molecules due to its azepine ring with a primary amide functional group that has two hydrogen bond donors and two acceptors. Succinic acid (SUC) is a common material in the pharmaceutical industry which can form cocrystals with CBZ. In this thesis, the CBZ-SUC cocrystal was used as an example for studying the preparation analysis-identification and thermodynamic analysis as the following.CBZ-SUC cocrystal was prepared by the methods of neat grinding, liquid-assisted grinding, slurrying and evaporation crystallization and the products were identified by powder X-ray diffraction, differential scanning calorimeter, Fourier transform infrared spectroscopy, electron microscope and chemical analysis. After establishing the qualitative and quantitative analysis of the cocrystal of the cocrystal, the effects of grinding time, solvent type and solvent volume on the cocrystal preparation were studied.The solubilities of CBZ (formⅢ), SUC (formβ) and their cocrystal in nine solvents were determined by the combination of the static method and chemical analysis. Results were correlated by semi-empirical equations, which show a good fit to the experimental data, and used to analyse the effects of cocrystal components on the cocrystal solubilities. The enthalpy and entropy of dissolution were also calculated.The dependence of the cocrystal solubility on the concentration of cocrystal components in solution were measured and explained by a cocrystal solubility product and by the binding constants of complexes formed in solution. According to solubility product and complex constant, the influence of temperature and solvents on the cocrystal dissolubility was explained from the intermolecular interaction. By Materials Studio, the binding energy between the CBZ-SUC cocrystal and the solvents were simulated and the mechanism for solvent effects on cocrystal dissolubility was investigated from the molecular level. The results show that the theoretical prediction of molecular simulation matches the experimental results better. This work provides a novel means of cocrystal ligind screening and solvent selection, which can guide the optimization of pharmaceutical cocrystal design, reduce the amount of experiments, shorten the research cycle and speed up the pharmaceutical process of research and development.In order to investigate how the cocrystals crystallized from different solvents, the ternary phase diagrams for the system of carbamazepine-succinic acid-ethanol or acetone at different temperature were constructed and the variation with temperature and solvents were discussed. Based on the diagrams, the reason for the cocrystal formation during grinding, the possible solid forms from solution crystallization and the prediction of unknown diagrams were obtained. The ternary phase diagrams help us understand how the cocrystal was crystallized from the solution and provides the theoretical basis for crystallization processes.