In-Line Monitoring of Carvedilol Crystallization Using Raman Spectroscopy

Real-time Raman spectroscopy was used to characterize the solvent-mediated polymorphic transition and cooling crystallization of carvedilol. Kinetically preferred Form II was transformed into thermodynamically stable Form I during solvent-mediated phase transitions in ethyl acetate. The transition rate into Form I increased with rising temperature; however, at 0 degrees C a solvate form (Form VII) appeared. In the case of cooling crystallizations, the Form H polymorph was formed at 16-9 wt % drug concentration, while metastable solvates crystallized from a diluted, 2.9 wt % solution. A new solvate form, Form V*, was identified during crystallization in ethyl acetate, which is presumably related to Form V (known as an ethyl methyl ketone solvate in the literature). This study demonstrates the advantages of in-line Raman spectroscopy for monitoring in situ pharmaceutical crystallization by detecting the intermediate polymorphic transitions, which is fundamental in the development and operation of industrial crystallization processes.