In Situ Monitoring of Polymorphic Transitions

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Abstract

An investigation of the feasibility of in situ monitoring of polymorphic transitions is presented. Focused beam reflectance measurement (FBRM) and particle vision and measurement (PVM) are used to study changes in crystal population and morphology during the transition of the δ-polymorph of d-mannitol to the thermodynamically stable β-form. The transformation is confirmed via off-line X-ray powder diffraction (XRPD). Nucleation and growth of β-form d-mannitol was detected and measured by FBRM/PVM when δ-form was added to a saturated solution of β-form d-mannitol. Raman spectroscopy is also introduced as an invaluable in situ identification technique for polymorphic crystallizations. The effect of particle size on the intensity of the Raman spectrum is investigated using slurries of d-mannitol and sucrose in toluene. Raman spectroscopy successfully distinguished a mixture of sucrose and d-mannitol in toluene, and a linear correlation between Raman peak intensity and solids content was observed for both. However, this linear relationship was not observed when the particle size distribution of sucrose was changed. It is clear that, especially in the case of many polymorphic conversions, information on the particle size distribution, along with additional structurally sensitive information such as Raman spectra, is essential in gaining a true understanding of the behaviour of the system.

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