Tropical Journal of Pharmaceutical Research

Original Research Article | OPEN ACCESS

An Efficient, Green Chemical Synthesis of the Malaria Drug, Piperaquine

Joseph MD Fortunak¹ , Stephen R Byrn², Brandon Dyson¹, Zita Ekeocha³, Tiffany Ellison¹, Christopher L King¹, Amol A Kulkarni⁴, Mindy Lee¹, Chelsea Conrad¹, Keeshaloy Thompson⁵

¹Department of Chemistry, Howard University, Washington, DC, 20059; ²Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, IN 47907 USA; ³St Luke Foundation â€“ Kilimanjaro School of Pharmacy, Industrial Pharmacy Training Unit, PO Box 481, Moshi, Tanzania; ⁴Department of Pharmaceutical Sciences, Howard University, Washington, DC, USA 20059; ⁵National Institute for Pharmaceutical Research & Development, Federal Ministry of Health, P.M.B. 21, Industrial Layout, Abuja, Nigeria.

For correspondence:- Joseph Fortunak Email: jfortunak@comcast.net

Received: 6 July 2012 Accepted: 11 June 2013 Published: 18 October 2013

Citation: Fortunak JM, Byrn SR, Dyson B, Ekeocha Z, Ellison T, King CL, et al. An Efficient, Green Chemical Synthesis of the Malaria Drug, Piperaquine. Trop J Pharm Res 2013; 12(5):791-798 doi: 10.4314/tjpr.v12i5.20

© 2013 The authors.
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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 commonly seen 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