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In-situ Raman spectroscopy for the in-line crystallization monitoring of entacapone

The physico-chemical properties of bioactive compounds and drugs may have a dramatic impact on the therapeutic efficacy and on the manufacturing of the final dosage forms and therefore it is crucial to develop tools that will enable process understanding and control in real time. Major limitations to improve the control of physical and chemical processes arise from the lack of versatile, accurate and reliable in-line sensors. Hence, new approaches and methodologies are needed for a better quality control and higher product efficiency. These should enable a non-invasive detection of different physical and chemical transformations of the reactants and products during the production process. FIGURE 1. Cis– and trans– stereoisomers of entacapone. Here we report on using in-line Raman spectroscopy for monitoring of the crystallization process of the drug entacapone (Figure 1). Entacapone, 2-cyano-N, N-diethyl-3-(3, 4-dihydroxy-5-nitrophenyl) propenamide, is a selective inhibitor of catechol-O-methyltransferase an enzyme responsible for the metabolism of L-dopa being a precursor to dopamine. It exists in the two stereoisomeric forms, cis- and trans-, both bioactive. Entacapone is clinically used and prescribed for the treatment of Parkinson’s disease. Raman spectroscopy has the advantage that it can easily be used for the remote detection through fiber optics facilitating the in-line monitoring of chemical reactions and crystallization processes thus generating data in real time. The combined use of in-situ Raman spectroscopy and multivariate analysis to analyze polymorphic forms of entacapone will be reported and discussed. ACKNOWLEDGMENTS The authors are acknowledged to Ana Kwokal for her helpful comments and suggestions. This work has been financially supported by The National Foundation for Science, Higher Education and Technological Development of the Republic of Croatia. REFERENCES 1. G. Fevotte, Int. J. Pharm. 241, 263-278 (2002). 2. J. Leppänen, E. Wegelius, T. Nevelainen, T. Järvinen, J. Gynther and J. Huuskonen, J. Mol. Struct. 562, 129-135 (2001). 3. A. Kwokal, T. T. H. Nguyen and K. J. Roberts, Cryst. Growth Des., 9, 4324-4334 (2009). 4. P. Novak, A. Kišić, T. Hrenar, T. Jednačak, S. Miljanić and G. Verbanec, in preparation.

in-line Raman spectroscopy; monitoring; crystallization process; entacapone

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