(174bc) PAT-Facilitated Crystallization Development and Particle Engineering Via Mechanistic Understanding

A development compound X which has a salt-formation step with a carboxylic acid was investigated to enhance understanding of its crystallization process. PAT Raman and FBRM were used to monitor the form transformation in real time and both were found to be indicative of the crystallization kinetics. A mechanistic model for solid form transformation was proposed based on the sequence of events involved and the mechanism was verified by the kinetic profiles revealed by Raman. A number of process variables were studied in a design of experiment (DoE) setting in order to identify the factors that impact the final attributes of the product such as particle size and morphology. The investigation, specifically through the precise quantitation by PAT, indicated the crystallization is primarily dictated by solvent composition and temperature. Other process variables such as seeds characteristics and acid addition rate were also evaluated and their effects on the outcome were found to be secondary. This insight helped steer the focus of development efforts to enhance the robustness of the process. A quantitative prediction model on particle size was extracted from the array of experiments and its accuracy was demonstrated at various spots of the parameter range covered by the study.