Designing Continuous Crystallization Protocols for Curcumin Using PAT Obtained Batch Kinetics

Abstract

Developing theory-informed standard operating procedures (SOPs) for the continuous crystallisation of pharmaceuticals still remains a bottleneck. For the continuous manufacturing of pharmaceuticals, the current methods rely on the laborious trial-and-error approach to identify process conditions such as the dilution rate (flow per unit volume of reactor) and initial supersaturation, where the productivity will be at maximum at steady-state conditions. This approach, while proven and considered to be useful, lacks or ignores the information obtained from batch kinetics. Herein for the first time, we propose a theoretical method to develop batch kinetics-informed theoretical procedures for the continuous manufacturing of a model compound curcumin in isopropanol. The theoretical approach uses batch kinetic constants to theoretically identify the optimum dilution rate and the corresponding mass of the model compound curcumin when crystallised, as well as its productivity at steady-state conditions as a function of initial supersaturation. The theory-informed procedures will serve as a valuable guideline to develop operating procedures for the continuous production of the target compound and thus eliminate the trial-and-error approach used to develop the protocols for the continuous manufacturing of pharmaceuticals. We also showed that our methods allow for the estimation of the dilution rate that corresponds to washout conditions (i.e., where all the crystals in the crystalliser will be washed out due to the high flow rate of the input stream) during the continuous manufacturing of crystals.