Polymorphic Concentration Control for Crystallization Using Raman and Attenuated Total Reflectance Ultraviolet Visible Spectroscopy

The aim of this study was to develop a new, easily performable feedback control of crystallization based on the exact polymorphic concentration (mass ratio of polymorph/solvent). The efficiency of the developed process control, utilizing combined signals of inline Raman and attenuated total reflectance ultraviolet visible sensors, was tested in a cooling crystallization of carvedilol. The solution concentration was determined according to multivariate calibration results of UV/vis spectroscopic detection, while the evaluation of the composition of the solid phase was performed by means of Raman spectroscopy assisted by the classical leastsquare method resulting in spectral concentrations. Polymorphic concentrations were obtained by calculating the current solid phase concentration from UV/vis data, and then this value was proportionated to the Raman spectral concentrations of different polymorphs. The real-time parallel evaluation of Raman and UV spectra was performed with the assistance of a Matlab program. The calculated polymorphic concentrations governed the control of cooling and reheating cycles of the crystallization using a programmable logic controller. The developed control approach was successfully adapted for the production of both pure polymorphic forms such as the kinetically preferred Form II or thermodynamically stable Form I.