Efficient assessment of combined crystallization, milling, and dissolution cycles for crystal size and shape manipulation

Abstract A 3-stage process, consisting of a combination of crystallization, milling, and dissolution stages for the selective manipulation of the size and shape of crystals, is investigated to characterize its performance when applied to different substances. To this aim, simulations are used to screen, via a parametric analysis, the effect of different compound properties and operating conditions on the size and shape of the final products. Through this analysis, characteristic trends of general validity are identified, thus allowing to define families of compounds with similar behavior and features. Based on these results, a set consisting of a small number of experiments is devised to fully characterize the outcome of the 3-stage process for a specific substance. An experimental validation is carried out by performing this set of experiments with two compounds, namely β l -Glutamic acid and γ d -Mannitol, thus assessing the suitability of this method for a comprehensive characterization of the process and its outcome. The information collected at the end of the different stages throughout all the experiments is further exploited to estimate the growth rates of γ d -Mannitol, in order to validate the observations made through simulations regarding the effect of growth kinetics on the process outcome. Finally, the model, fitted to the experimental evidence collected, has been used to further investigate and characterize the design space.