Dissolution, Nucleation, Crystal Growth, Crystal Aggregation, and Particle Breakage of Amlodipine Salts: Modeling Crystallization Kinetics and Thermodynamic Equilibrium, Scale-up, and Optimization

Abstract

Both in the pharmaceutical industry and in pharmacology, crystallization and dissolution processes play an important role in the production and physiological action of active pharmaceutical ingredients. For the first, recrystallization or other phase transformations present an indispensable step in downstream separation and purification processing, while for the second, solubility is of vital importance for drug delivery systems such as tablets. In the present study, the anhydrous form of amlodipine was investigated from its basic structural and conformational characteristics using molecular modeling, to the laboratory-scale formation of its solid phase from solution, and finally, to industrial-size operation by applying models, based on the hydrodynamic characteristics in the crystallizer due to mixing (computational fluid dynamics (CFD)), transport phenomena (specifically heat transfer), and population balance modeling. Simulations revealed that an efficient process intensification and control may be realized through the seeding and widening of the metastable zone (nucleus absence albeit supersaturation), providing a uniform and monodisperse size distribution.