(343d) Application of in-Situ Raman Spectroscopy in Monitoring the Dynamic Trends of Polymorphic Transformation and Hydrogenation Reaction

Application of in-situ Raman spectroscopy in monitoring the dynamic trends of polymorphic transformation and hydrogenation reaction

Haitao Zhang, Bob Prytko, Mike Sizensky, Kostas Saranteas

Chemical Process Research & Development, Sunovion Pharmaceuticals Inc., 84 Waterford Drive, Marlborough, Massachusetts 01752, U.S.A.

Abstract

During the last decade many novel manufacturing practices such as Process Analytical Technology (PAT), Quality by Design (QbD), and Real Time Release (RTR) have been introduced to the pharmaceutical industry, and they are expected to be an effective aid to pharmaceutical manufacturing. On the basis of a recent FDA directive, this mode of operation will transform the manufacturing aspect of the pharmaceutical industry.

In crystallization processes, control and optimization of the polymorph formation requires in-situ quantitative measurement of the concentration of different polymorphs. Herein, we report the application of in-line Raman spectroscopy to monitor the polymorphic transformation of DSP-6373 during crystallization process. Kinetically preferred Form II of DSP-6373 was transformed into thermodynamically stable Form I during a solvent-mediated phase transition in isopropanol. The feasibility of identifying the differences between the two polymorphs has been demonstrated by collecting and comparing the Raman spectra of the pure polymorphic crystals. A calibration curve has been built based on different ratios of the polymorphs. The in-line Raman spectroscopy can effectively identify the two forms of crystals in solution as well, which allows it to be used to capture the dynamic trend of the polymorphic transformation.

This study experimentally demonstrates the advantages of using in-line Raman spectroscopy for monitoring in-situ pharmaceutical crystallization by detecting the polymorphic transformation, which is fundamental in the development and operation of industrial crystallization processes. A second application of in-line Raman spectroscopy technology was also explored for the hydrogenation reaction of an enacetamide to an acetamide in order to monitor the real time performance of the reaction and obtain in-line kinetic data.