Crystallization monitoring by Raman spectroscopy: Simultaneous measurement of desupersaturation profile and polymorphic form in flufenamic acid systems

In this study, the application of Raman spectroscopy to quantitative in-line monitoring of the crystallization from solution of an enantiotropic polymorphic system, flufenamic acid, is explored. Separate feasibility studies were performed to evaluate the utility of Raman spectroscopy to quantitatively monitor changes in solution concentration and to measure polymorphic composition. The crystallization of flufenamic acid was then monitored as a function of temperature and time using an immersion probe coupled to a Raman spectrometer. The spectral data contained information about both the solution phase and the crystallized solids. Using standard data analysis techniques, solution and solids information could be deconvoluted. Changes in solute concentration as a function of time were quantified from the Raman data and showed good agreement with results from other techniques used for corroboration. The polymorphic forms initially crystallizing from solution, in the presence and absence of seeds, could be clearly identified. Furthermore, the kinetics of the conversion of the metastable form to the stable form could be readily followed. This study illustrates the complex nature of the crystallization process, the ability of Raman spectroscopy to monitor this process, and the potential for this technique to aid in process optimization and control.