An investigation into the effect of impurities on the crystallization of curcumin

This thesis investigates the influence of two structurally related impurities, Demethoxycurcumin and Bisdemethoxycurcumin, on the crystallization of Curcumin. Firstly, a purification technique was designed and used to separate the three curcuminoids from each other. Pure fractions of Curcumin (100%), Demethoxycurcumin (98.6%) and Bisdemethoxycurcumin (98.3%) were isolated by column chromatography applying a stepwise increase in the methanol concentration. Using these purified fractions, an investigation of the solubility of Curcumin in pure propan-2-ol solution and in impure propan-2-ol solution containing dissolved Demethoxycurcumin or Bisdemethoxycurcumin impurity at different impurity concentrations was investigated. It was observed that Bisdemethoxycurcumin has a stronger influence on decreasing the solubility of Curcumin in propan-2-ol in comparison to Demethoxycurcumin. A ‘competing effect’ between Curcumin and dissolved impurity molecules for propan-2-ol solvent molecules was implied in explaining this decrease in the solubility. Nucleation studies were completed to examine the influence of Demethoxycurcumin and Bisdemethoxycurcumin on the primary nucleation of Curcumin. The induction time for nucleation was measured at different Curcumin driving forces and impurity concentrations and the results were analysed by the classical nucleation theory. Both Demethoxycurcumin and Bisdemethoxycurcumin delayed the nucleation of Curcumin by prolonging the induction times. The two impurities decreased the pre-exponential factor for Curcumin nucleation, while having a negligible influence on the interfacial energy of Curcumin in propan-2-ol suspension. With regards to nucleation, density functional theory and molecular dynamic computations indicated that the binary interactions of Curcumin‒Demethoxycurcumin and Curcumin‒Bisdemethoxycurcumin are stronger than the respective binding between two Curcumin molecules, which suggests that a certain energy barrier has to be overcome in order to remove the impurity molecules from the Curcumin structures in solution in order for the Curcumin pre-nuclei clusters to form a stable nucleus making clusters containing impurities more likely to dissolve rather than advancing to stable crystals. The growth rate of pure Curcumin particles in pure and impure (containing Demethoxycurcumin and Bisdemethoxycurcumin impurities) supersaturated solutions was determined by seeded isothermal desupersaturation experiments at different Tcryst. In situ (ATR) ultraviolet-visible spectroscopy and focused beam reflectance measurements were used to monitor the solution concentration over time and to ensure that no nucleation was occurring. The growth of Curcumin Form I spheres was significantly slower than the crystal growth of smaller pharmaceutical compounds in organic solvents. A solid-liquid interfacial energy of 2.65 ± 0.1 mJ.m-2 was determined by fitting the birth and spread model to the experimental desupersaturation data. The product Curcumin particles collected after growth were denser and more spherical in shape in comparison to the Curcumin seed particle. The presence of Demethoxycurcumin and Bisdemethoxycurcumin slow down the growth rates of Curcumin. It was hypothesized that Curcumin grows by a 3-D nucleation growth mechanism in the presence of the impurities, the slow step been the formation of the stable nucleus. A higher interfacial energy value of Curcumin was obtained in the presence of the two impurities. The product particles collected after growth in the presence of Demethoxycurcumin or Bisdemethoxycurcumin impurities had a rougher and more porous particle surface in comparison to Curcumin crystals grown in pure solutions which looked to be denser and less porous.