Implementation of Raman Signal Feedback to Perform Controlled Crystallization of Carvedilol

This study indicates that real-time Raman spectroscopy is more than just an effective tool for monitoring drug crystallizations. The results verify that fibre-optic-coupled Raman spectroscopy can be used not only for monitoring processes but also for ensuring the production of the desired polymorphs by continuous feedback of the polymorph signal in the course of crystallization procedures. Cooling crystallization of an active pharmaceutical ingredient was performed to test the feedback method, during which the kinetically preferred and desired Form II crystal structure was produced. If, however, a thermodynamically stable undesired polymorph is present as an impurity, it will influence the characteristics of the end product. The aim of the control, based on Raman-signal feedback, was to ensure that the quality of the drugs was maintained in crystallization processes, despite such disturbing influences. The feedback control was based on the development of communication between a Raman spectroscope and a programmable logic controller. The control was performed with the aid of the ratio of two Raman intensities, characteristic of the two polymorphs (Form I and Form II). In addition, the control was able to handle the changes in Raman intensity caused by crystal size alteration. The developed model demonstrates a new way to meet the recent FDA directives concerning Process Analytical Technology (PAT).