Speciation of antimony in injectable drugs used for leishmaniasis treatment (Glucantime®) by HPLC-ICP-MS and DPP
- 458 Downloads
Meglumine antimonate is the active of Glucantime® used for the treatment of leishmaniasis, a tropical disease caused by parasitic protozoa, and it is estimated that 12 million people worldwide are affected. This drug mainly contains Sb(V) under the form of an organic complex with N-methylglucamine (NMG). During the synthesis of this molecule, traces of Sb(III) may be present, also probably complexed. Due to the fact that Sb(III) is considered more toxic than Sb(V), it is important to evaluate the Sb(III) concentration in the drug samples. In the literature, very different concentrations for residual concentrations of Sb(III) in the drug ampoules are found. Therefore, to have a true insight of antimony speciation, two independent analytical methods were developed in this work. We used an anion exchange method coupled with inductively coupled plasma mass spectrometry (ICP-MS) which was cross-referenced with an electrochemistry method (differential pulse polarography (DPP)) that could be used for routine analysis on the production site. To obtain Sb species in detectable forms, the complexes between Sb species and NMG need to be broken. This was obtained by diluting samples in hydrochloric acid in deaerated conditions to avoid Sb redox reactions. For the two analytical methods, the HCl concentration was optimized to obtain simultaneously a complete destruction of the complexes as well as limited redox reactions for Sb(V) and Sb(III) released species. For high-performance liquid chromatography (HPLC)-ICP-MS, a dilution with 5 M HCl gives the better results. The side reaction is an oxidation of Sb(III) which can be limited by the removal of oxygen. When DPP is used, the major problem is the reduction of Sb(V) which is present in high amount in the samples. Working with 0.6 M HCl allows this problem to be minimized. When applied to different lots of Glucantime®, Sb(III) concentration values are in good agreement for the two analytical methods, with, for HPLC-ICP-MS, the advantage of the simultaneous detection of both Sb redox species.
KeywordsAntimony Speciation DPP HPLC-ICP-MS Drug Leishmaniasis
The authors are grateful to different people from Sanofi for their valuable assistance in this study, especially Philippe Cleon and Christelle Plantard (Neuville-sur-Saône, France) for the structure elucidation of NMGA complexes, Loïc Planas (Porcheville, France) for synthesis of the NMG-Sb(III) complex, Zsolt Dombrady and Attila Nemeth (Újpest Site Tó utca, Hungary) for the synthesis of NMGA–citric acid complexes, Nicolas Invernizzi for the study about dissolution studies of antimony pentachloride (Vitry-sur-Seine, France) and Laurent Nicolas from Hypsoma (France) for starting the study on Sb speciation in N-methylglucamine antimonate.
- 1.Leishmaniasis (2010) In: Crompton DWT (ed) Neglected tropical diseases: working to overcome the global impact of neglected tropical diseases, WHO Report. WHO, Geneva, 91–96. http://www.who.int/neglected_diseases/2010report/en/
- 4.Haldar AK, Sen P, Roy S (2011) Use of antimony in the treatment of leishmaniasis: current status and future directions. Mol Biol Int. doi: 10.4061/2011/571242
- 6.Roberts WL, McMurray WJ, Rainey PM (1998) Antimicrob Agents Chemother 42:1076–1082Google Scholar
- 8.Franco MA, Barbosa AC, Rath S, Dorea JG (1995) J Trop Med Hyg 52:435–437Google Scholar
- 24.ICH (2005) Validation of analytical procedures: text and methodology. ICH Harmonised tripartite Guideline. http://www.ich.org/products/guidelines/quality/article/quality-guidelines.html. Accessed 5 May 2012