In Situ Monitoring and Modeling of the Solvent-Mediated Polymorphic Transformation of l-Glutamic Acid

In this paper, we present the application of four different in situ analytical techniques to monitor the solvent-mediated polymorphic transformation of l-glutamic acid. Focused beam reflectance measurement (FBRM) and particle vision and measurement (PVM) have been used to track the chord length and morphology of the crystals over the course of the transformation. The polymorphic forms present have been monitored using Raman spectroscopy, while attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy has been used to measure the liquid-phase concentration profile. The combination of the different in situ data was used to identify the fundamental phenomena of nucleation and growth that govern the process. Moreover, the measurement data were combined with a mathematical model based on population balance equations and the fundamental equations describing the kinetics of nucleation and growth of both polymorphs. This combination allowed for the estimation of the characteristic nucleation and growth rates of the two polymorphic forms, while the dissolution process of the metastable polymorph was estimated using a Sherwood correlation. Finally, the experimental results obtained with different initial conditions and their simulation allowed for the validation of the population balance model and for a deeper understanding of the transformation process.