Influence of solvent and impurity on the crystallization and properties of crystallized products

Many pharmaceutical processes involve crystallization from solution. In this thesis, the influence of the solvent and impurities on the crystallization process is described, using the solvent-mediated polymorphic transformation of sulfamerazine as the model system. The transition temperature of sulfamerazine polymorphs I and II was estimated from the heat of solution and solubility data to be 52.5°C. The polymorphic transformation rate from metastable polymorph I to stable polymorph II is controlled by a balance of solubility and strength of hydrogen bonding interactions between the solvent and the solute. Trace amounts of structurally-related impurities significantly inhibit the polymorph transformation in solution by decreasing the crystallization rate of Polymorph II. The calculated binding energy of the impurity to the surface of sulfamerazine Polymorph II predicts the rank order of the inhibitory effect of the impurity. The relationship between the inhibitory effect of the impurity and the concentration of the impurity in the solution can be described by a model based on the Langmuir adsorption isotherm.; The relationship between the extent of impurity incorporation and the particle size was also determined. For the three model systems with segregation coefficients <1, larger crystals incorporate more impurities and liquid inclusions than smaller particles in the same batch. However, the incorporation of impurity follows a mechanism that is different from the formation of liquid inclusions.; The effects of incorporated impurity on the physicochemical properties of the host crystals are examined. (+)-(SS)-Pseudoephedrine hydrochloride, when crystallized from aqueous solution in the presence of (-)-(RS)-ephedrine hydrochloride, can take up the latter into its crystal lattice with a segregation coefficient of 0.31. The impure crystals possess a higher enthalpy and entropy than the pure crystals. However, the intrinsic dissolution rate of the doped crystals is lower than that of pure crystals, suggesting the formation of a stable solid solution.; These studies emphasize the need for careful control of the effects of the solvent and impurity during various pharmaceutical processes involving crystallization to obtain the desired products.