A Calibration-Free Application of Raman Spectroscopy to the Monitoring of Mannitol Crystallization and Its Polymorphic Transformation

Raman spectroscopy is one of a number of potential in situ process analysis technologies (PATs) for application in crystallization processes. In this paper, the use of Raman spectroscopy in the cooling crystallization of mannitol is investigated. Mannitol has three known polymorphs (alpha, beta, and delta) that can be assessed using Raman spectroscopy. Although several multivariate spectroscopic methods for measuring both the dissolved concentration and the polymorphic form using Raman exist, their application requires significant calibration and/or that several assumptions be made about the relationship between the concentration and the Raman spectra. In this paper, a novel and simple calibration-free univariate method for monitoring supersaturation during the cooling crystallization of mannitol is demonstrated. The use of the method to successfully monitor the transformation process of the metastable alpha form to the stable beta form in aqueous solution is also presented.