Characterization of Sodium Stibogluconate by Online Liquid Separation Cell Technology Monitored by ICPMS and ESMS and Computational Chemistry

Abstract

High-performance liquid chromatography (HPLC), mass spectrometry (MS), and computational chemistry has been applied to resolve the composition and structure of the Sb species present in dilutions of Pentostam, a first-line treatment drug against Leishmania parasites. Using HPLC-inductively coupled plasma-MS and electrospray-MS, it was shown that the original drug consists of large Sb(V)-glyconate complexes of polymeric nature that degrade upon dilution. In dilution solution, the drug is a mixture of noncomplexed Sb(V), large polymeric complexes as well as several low molecular mass Sb(V)-glyconate complexes of various stoichiometry (1:1, 1:2, 1:3, 2:2, 2:3, 2:4, 3:3, 3:4). The 1:1 complex became the most abundant low molecular mass Sb(V) complex with dilution time. A novel mixed-mode chromatographic system was applied in order to separate complexes of various stoichiometry and isomers. Density functional theory was used to study the structure of the 1:1 Sb-gluconate complex with three or four solvent molecules bound. By computing the structures and the free energies of the various possible isomers in aqueous solvation models, the most likely structures of the species were deduced. Importantly, 6-coordination is always preferred over 5-coordination, and the species commonly adopt conformations involving tris-coordination of deprotonated hydroxyl groups from gluconate.

Use of Antimony in the Treatment of Leishmaniasis: Current Status and Future Directions

“…Osmolarity measurement suggested the predominance of 1 : 1 Sb-NMG and Sb-SSG complexes in diluted samples [25]. This interpretation was further in agreement with the HPLC-inductively coupled plasma-MS and ESI-MS analyses [27]. …”

Quantitative HPLC-ICP-MS analysis of antimonyredox speciation in complex sample matrices: new insights into the Sb-chemistry causing poor chromatographic recoveries

“…19 Likewise, the drug meglumine antimonate is oligomeric due to chelation by vicinal hydroxy functions. 20 Several types of organic Sb(V) polymers are described where Sb is bound via oxygen atoms in a non-chelate fashion, e.g.…”

The prevalence of metal-based drugs as therapeutic or diagnostic agents: beyond platinum

“…ESI-MS results and molecular sieve experiments have indicated that it, like megulmine antimoniate, exists in several oligomeric forms in solution as (Sb-GLU) n -GLU where GLU is the ligand gluconate. 80,81 Dilute solution osmolarity measurements indicate that both meglumine antimoniate and sodium stibogluconate form simple 1 : 1 complexes in solution, the proposed structures of which are displayed in Fig. 4.…”