PAT-Facilitated Pharmaceutical Crystallization Development through Mechanistic Understanding

Process analytical technology (PAT; Raman spectroscopy and FBRM) was used to monitor the salt formation step of a development compound in real time. The data obtained were used to understand the crystallization kinetics and behavior. A mechanistic model was proposed on the basis of the sequence of events, and the mechanism was verified by the Raman profiles. Several operational parameters were studied in a matrix setting in order to identify the factors that affect the quality attributes of the final product such as particle size and morphology. The kinetic characterization through PAT revealed that the process is primarily influenced by temperature and solvent composition and that the acid addition rate and agitation speed were found to have a marginal effect. A regression model on API particle size was extracted from the data set, and its accuracy was verified at various set points of the parameter range covered in the investigation. The workflow adopted by this study illustrates how process knowledge generated by a combination of PAT and modeling, as well as a multistaged experimental plan executed on the basis of learning from technical insight, can efficiently lead to the process control as required under the current regulatory frameworks.