An Investigation of Solvent-Mediated Polymorphic Transformation of Progesterone Using in Situ Raman Spectroscopy

Abstract

Many analytical techniques, such as differential scanning calorimetry (DSC), X-ray diffraction (XRD), infrared spectroscopy (IR) and Raman spectroscopy can be used to differentiate between crystalline polymorphs of the same chemical entity. While all of these techniques are routinely applied to off-line analysis of materials, Raman spectroscopy has the advantage over these other techniques in that Raman technology currently exists for in situ monitoring of the solid-phase behavior within a mixed suspension of liquid and solid. In this work, we present our results from an in situ Raman study, demonstrating the solvent-mediated polymorphic phase transformation of progesterone. In situ Raman analysis has shown that the appearance of Form I progesterone is always preceded by the formation of Form II progesterone. Phase transformation rates were found to increase monotonically as the temperature increases, which indicates that the polymorphic system is monotropic. Form I was found to be thermodynamically more stable than Form II, while Form II was found to be kinetically favored over Form I. The results from this study are consistent with Ostwald's law of stages and lead to an in-depth understanding of the polymorphic transformation process of progesterone. The in situ monitoring capabilities of Raman spectroscopy have allowed us to define the processing parameters required to control the morphology of crystalline progesterone.