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Stereodynamic Investigation of Labile Stereogenic Centres in Dihydroartemisinin
Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza Università di Roma, P. le Aldo Moro 5, 00185 Roma, Italy
Analytical Development, R&D Department, sigma-tau S.p.A., Via Pontina km 30,400, 00040 Pomezia, Italy
* Authors to whom correspondence should be addressed.
Received: 1 January 2010; in revised form: 25 January 2010 / Accepted: 4 March 2010 / Published: 5 March 2010
Abstract: Since its identification in the early 1970s, artemisinin, as well as semi-synthetic derivatives and synthetic trioxanes, have been used in malaria therapy. Reduction of artemisinin by NaBH4 produced dihydroartemisinin (DHA), and yielded a new stereochemically labile centre at C-10, which, in turn, provided two interconverting lactol hemiacetal epimers (namely a and b), whose rate of interconversion depends on buffer, pH, and solvent polarity. Since interconversion of the two epimers occurred on a chromatographic time-scale, this prompted a thorough investigation of the phenomenon as a crucial requisite of any analytical method aimed at quantitating this family of drugs. In this critical review we discuss the current importance of the on-column epimerization of DHA in the development of analytical methods aimed at quantifying the drug, with the purpose of identifying the optimal conditions to minimize on-column epimerization while achieving the best selectivity and efficiency of the overall separation.
Keywords: Dihydroartemisinin (DHA); on-column epimerization; cryo-HPLC; dynamic HPLC (DHPLC); computer simulation
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D’Acquarica, I.; Gasparrini, F.; Kotoni, D.; Pierini, M.; Villani, C.; Cabri, W.; Di Mattia, M.; Giorgi, F. Stereodynamic Investigation of Labile Stereogenic Centres in Dihydroartemisinin. Molecules 2010, 15, 1309-1323.
D’Acquarica I, Gasparrini F, Kotoni D, Pierini M, Villani C, Cabri W, Di Mattia M, Giorgi F. Stereodynamic Investigation of Labile Stereogenic Centres in Dihydroartemisinin. Molecules. 2010; 15(3):1309-1323.
D’Acquarica, Ilaria; Gasparrini, Francesco; Kotoni, Dorina; Pierini, Marco; Villani, Claudio; Cabri, Walter; Di Mattia, Michela; Giorgi, Fabrizio. 2010. "Stereodynamic Investigation of Labile Stereogenic Centres in Dihydroartemisinin." Molecules 15, no. 3: 1309-1323.