An investigation of solvent mediated polymorphic transformation of progesterone using in situ Raman spectroscopy

Many analytical techniques, such as differential scanning calorimetry (DSC) , X-rag diffraction (XRD), infrared spectroscopy (IR) and Raman spectroscop y can be used to differentiate between crystalline polymorphs of the same c hemical 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 mon itoring 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, d emonstrating the solvent-mediated polymorphic phase transformation of proge sterone, In situ Raman analysis has shown that the appearance of Form I pro gesterone is always preceded by the formation of Form II progesterone, Phas e transformation rates were found to increase monotonically as the temperat ure increases, which indicates that the polymorphic system is monotropic, F orm I was found to be thermodynamically more stable than Form II, while For m 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, Th e in situ monitoring capabilities of Raman spectroscopy have allowed us to define the processing parameters required to control the morphology of crys talline progesterone.