Towards a Crystalline Product Quality Prediction Method by Combining Process Modeling and Molecular Simulations

Abstract

It is shown for the first time that a combination of molecular simulations and process modeling can be used to predict crystalline product quality aspects such as the polymorphic fraction and crystal size distribution. Using molecular simulations the interfacial energy of 3D nuclei and the step free energy of 2D nuclei on crystal surfaces of different polymorphs are determined. These result in the nucleation and growth behavior of the polymorphs as a function of the supersaturation. The supersaturation development during polymorph crystallizations can be accounted for using dynamic process modeling. Furthermore, this study clearly demonstrates that a deeper understanding of polymorph crystallization can be obtained by combining research on a molecular scale with that on a process scale. Molecular simulations show, for instance, that there is no simple relationship between experimental solubility and apparent interfacial energy of the polymorphs.

An atomistic simulation towards elucidation of operating temperature effect in CO2 swelling of polysulfone polymeric membranes

“…The satisfactory accordance demonstrates that the proposed methodology in present study is of sufficient accuracy to characterize specific interaction between CO2 and functional groups of polymeric chain. This study demonstrates that the findings of atomistic behaviour at a microscopic scale can be extended to extrapolation of material properties applied to new applications and operation windows at a macroscopic level [114][115][116], which emphasizes the importance of molecular modelling in present study.…”

Keimbildung organischer Kristalle aus molekularer Sichtweise

“…Selbstverständlich besteht hier die Gefahr der Vermutung, das makroskopische Aussehen einer Kristallform könne direkt mit Vorgängen verknüpft werden, die während der Keimbildung stattfinden, obwohl doch in Wirklichkeit die relativen Kristallwachstumsraten verfügbarer Polymorphe eine wichtige Rolle spielen können 20. 49 Diese Gefahr ist vielen Versuchen zueigen, das empirische “Stufengesetz” von Ostwald zu erklären. Dies wird von Hammond et al 50.…”

Crystal Growth Kinetics of Pharmaceutical Compounds

“…More recently, nucleation and growth of organic molecules, such as pharmaceuticals, have attracted attention, yet the fundamental understanding is still weak. As recently emphasized, , linking the macroscopic appearance of crystals only to the nucleation process can result in a misapprehension, since the crystal growth rate as well determines the crystallization outcome, especially in polymorphic systems. , Crystal growth rates increase with increasing supersaturation and temperature and depend on physicochemical properties of solute and solvent. The nature and strength of intermolecular interactions between solute and solvent, which influence the solvation shell, solute intramolecular interactions, and solute molecular conformations, have been related to the ease of nucleation, , as well as to the rate of crystal growth, e.g., of piracetam, salicylic acid, and tolbutamide .…”