Comprehensive kinetic model for the dissolution, reaction and crystallization processes involved in the synthesis of aspirin

Kinetic modeling of batch reactions monitored by in-situ spectroscopy has been shown to be a helpful method for developing a complete understanding of reaction systems. Much work has been done to demonstrate the ability to model dissolution, reaction and crystallization processes separately, however little has been done in terms of combining all of these into one comprehensive kinetic model. This paper demonstrates the integration of models of dissolution, temperature-dependent solubility and unseeded crystallization driven by cooling into a comprehensive kinetic model describing the evolution of a slurry reaction monitored by in-situ ATR UV/Vis spectroscopy. The model estimates changes in the volume of the dissolved fraction of the slurry by use of the partial molar volume of the dissolved species that change during the course of reagent addition, dissolution, reaction and crystallization. The comprehensive model accurately estimates concentration profiles of dissolved and undissolved components of the slurry and thereby, the degree of undersaturation and supersaturation necessary for estimation of the rates of dissolution and crystallization. Results were validated across two subsequent batches via offline HPLC measurements.