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Polymorphic conversion monitoring using real-time Raman spectroscopy 


*Corresponding author
Hovione FarmaCiencia SA, Sete Casas, 2674-506 Loures, Portugal


This article reports the application of in-line Raman spectroscopy as a PAT (Process Analytical Technology) tool to monitor a urea formation at pilot scale. This reaction was critical since it involved the formation of different polymorphic forms with distinct solubility properties, which impacted the overall process yield and purity. Raman spectroscopic data collected during the reaction allowed the tracking of polymorphic conversion, providing better insight into the process and offering a faster analytical response than conventional in-process testing by X-ray powder diffraction. Once integrated in an appropriate control strategy, this PAT tool enabled an enhanced process step control and helped achieve the targeted product purity and yield.


Since polymorphs first identification the search for methods to monitor and control their formation has been of great interest in the pharmaceutical industry. The existence of different polymorphic forms of a product may allow a patent extension as the polymorphic forms of an active pharmaceutical ingredient (API) are patentable. Typically, polymorphic forms occur when products are crystallized or precipitated from a reaction mixture and the analytical techniques most commonly used to identify them are X-ray powder diffraction (XRPD), Infra-red or Raman spectroscopy and Differential Scanning Calorimetry (DSC) (1). Both XRPD and DSC analyses are usually carried out off-line and are not likely to have a fast response (average time of analysis is one hour). On the other hand, Raman spectroscopy is a fast and accurate analytical technique that allows effective monitoring and control of industrial processes, pursuing the concept of an innovative state in Pharmaceutical Manufacturing where PAT and Quality by Design (QbD) are applied (2-8). The concept and terminology QbD have become part of the common language of those working in the pharmaceutica ...