Mixed-Suspension, Mixed-Product Removal Studies of Ciprofloxacin from Pure and Crude Active Pharmaceutical Ingredients: The Role of Impurities on Solubility and Kinetics

Despite the known effects of foreign species on crystallization and the frequently large number of impurities present in multistep pharmaceutical syntheses, the early characterization of continuous crystallization operations may be limited by the availability of representative crude material. As part of the development of an end-to-end process for ciprofloxacin HCl monohydrate, this work evaluates the impact of upstream impurities on mixed-suspension, mixed-product removal (MSMPR) crystallization kinetics. The kinetic parameters for nucleation and crystal growth in MSMPR crystallization have been estimated for the commercial, purified active pharmaceutical ingredient (API), as well as crude API containing approximately 60 unknown impurities. Results show that, while the upstream impurities did not have a significant impact on the nucleation rate, both the temperature-dependent growth rate coefficient and the growth activation energy decreased in crude API crystallization. This behavior implies that the effects of impurities cannot simply be lumped into the temperature-independent rate coefficients. When evaluating the prediction capabilities of purified API data for crude crystallization, it was observed that a reasonable prediction of crystallization yield and crystal purity demands accurate knowledge on the thermodynamics of crude crystallization. Moreover, kinetics of crude API crystallization must be known to confidently predict the steady state particle size.