Polymers and Solvent-Induced Polymorphic Selection and Preferential Orientation of Pyrazinamide Crystal

Induced crystallization plays an important role in polymorphism control of active pharmaceutical ingredients. Crystallization processes of pyrazinamide on templates of glass, nylon-66 (PA66), polytetrafluoroethylene (PTFE), and polyethylene terephthalate (PET), and polyformaldehyde (POM) films were investigated by evaporation in solvents of acetone, dioxane, and acetonitrile. The δ crystals or α + δ mixtures were obtained with glass, PTFE, PET, and POM in all solvents and with PA66 in dioxane, while only the PA66 finally induced the α crystals of pyrazinamide in acetone and acetonitrile. The templates and the solvents also influenced preferential orientation of pyrazinamide crystals; i.e., the PA66 weakened the 27° peaks of powder X-ray diffraction. The relation between contact angle of the solvents and the templates with pyrazinamide polymorph outcome has been discussed. Adsorption energy and the dynamics of two-phase boxes were used to explore the relation between the pyrazinamide polymorphs and the PA66. Molecular simulation calculations were conducted to provide molecular and thermodynamic insight. 1 H– 1 H NOESY spectra showed a dimer of pyrazinamide in the solution with H-bonds, which indicated the stronger influence of thermodynamics than kinetics in the crystallization process. This study provides a better understanding of the mechanism of polymer-induced heterogeneous nucleation and crystal growth, therefore leading to more accurate control of polymorphs of active pharmaceutical ingredients.