Author/Authors :
Fortunak, Joseph M. D. Howard University - 1Department of Chemistry, USA , Byrn, Stephen R. Purdue University - Department of Industrial and Physical Pharmacy, USA , Dyson, Brandon Howard University - 1Department of Chemistry, USA , Ekeocha, Zita St Luke Foundation - Kilimanjaro School of Pharmacy - Industrial Pharmacy Training Unit, Tanzania , Ellison, Tiffany Howard University - 1Department of Chemistry, USA , King, Christopher L. Howard University - 1Department of Chemistry, USA , Kulkarni, Amol A. Howard University - Department of Pharmaceutical Sciences, USA , Lee, Mindy Howard University - 1Department of Chemistry, USA , Conrad, Chelsea Howard University - 1Department of Chemistry, USA , Thompson, Keeshaloy Howard University - 1Department of Chemistry, USA
Abstract :
Purpose: To provide a robust, efficient synthesis of the malaria drug piperaquine for potential use in resource-poor settings. Methods: We used in-process analytical technologies (IPAT; HPLC) and a program of experiments to develop a synthesis of piperaquine that avoids the presence of a toxic impurity in the API and is optimized for overall yield and operational simplicity. Results : A green-chemical synthesis of piperaquine is described that proceeds in 92 – 93 % overall yield. The chemistry is robust and provides very pure piperaquine tetraphosphate salt ( 99.5 %). The overall process utilizes modest amounts (about 8 kg/kg) of 2-propanol and ethyl acetate as the only organic materials not incorporated into the API; roughly 60 % of this waste can be recycled into the production process. This process also completely avoids the formation of a toxic impurity commonlyseen in piperaquine that is otherwise difficult to remove. Conclusion: An efficient synthesis of piperaquine is described that may be useful for application in resource-poor settings as a means of expanding access to and reducing the cost of ACTs.
Keywords :
ACTs , Dihydroartemisinin Piperaquine , Dihydroartemisinin , Green Chemistry , Malaria , Piperaquine.
