Understanding a Reactive Crystallization Through Thermodynamic and Kinetic Modeling

Process development of active ingredients and intermediates relevant to the agrochemical and pharmaceutical industry often involves reactive crystallization. These synthesis schemes are usually complicated by the relative influences of chemical reaction and crystallization on the outcome of the process. Often, the solution conditions that result in a good reaction with desirable product formation and high yield are not the optimal conditions for isolating the formed product in a solid form with high recovery. Here, we discuss a case study on the synthesis of an agrochemical intermediate wherein the target molecule is prone to oiling out as soon as the reaction progresses, thus complicating the subsequent execution of the process scheme.

To address this situation, systematic experiments that probed the reaction kinetics and crystallization thermodynamics (without mutual influence) were carried out. These data were used to build a reaction kinetic model and a phase diagram model for the compound. Combining these two modules into a master reactive crystallizer model, the proximity and potential intersection of the process path and the liquid-liquid phase separation (oiling out) boundaries were readily characterized. The analysis revealed that in the existing process scheme the reaction and crystallization were separated in time resulting in a rapid crystallization event during the later part of the process. Alternate process schemes that can reduce / eliminate oiling out and distribute crystallization evenly throughout the time course of the reaction were identified. The approach discussed here highlights the effectiveness of first-principles modeling in providing the team with critical insights needed for identifying a robust process scheme, thus reducing empiricism in process development.