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 least-square 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.