Crystallization of fesoterodine fumarate active pharmaceutical ingredient: Modelling of thermodynamic equilibrium, nucleation, growth, agglomeration and dissolution kinetics and temperature cycling

Abstract

The crystallization of active pharmaceutical ingredients (API) is an important, but complex unit operation in drug manufacturing industry, due to the diverse chemical nature of medicinal formulation compounds, several physicochemical phenomena that take place during particle formation process, and multi-phase governing resistances. This research paper presents a combined experimental–modelling approach to understanding fesoterodine fumarate crystallization and dissolution in 2-butanone. A rigorous in-house mechanistic model algorithm that includes calibration, thermodynamic equilibrium description, energy, mass and population balance equations, heat transfer limitations, and ordering, agglomeration and detachment step kinetics was developed. On the basis of experimentally-determined saturated solubility, a specified initial number of designed dissolution and cooling crystallization experiments was performed, monitored by attenuated total reflection Fourier-transform infrared (ATR–FTIR) spectroscopy, focused beam reflectance measurement (FBRM) technique and microscopy. The estimated kinetic parameters of transport, nucleation, crystal lattice growth, agglomeration and dissolution were evaluated by fitting the measured/simulated concentration curves with crystallite size distributions. Correlation was validated with additional trial results, observing a rather good agreement. The behaviour of the component during validations’ temperature cycling was thoroughly examined by simulations to achieve a solid final insight into mechanisms, which may aid further production development, optimization, as well as scale-up.