Multivariate Optimization Applied to the Synthesis of Meglumine Antimoniate with Low Levels of Trivalent Antimony

Abstract

Meglumine antimoniate (MA) is a pentavalent antimony (SbV) drug recommended for the treatment of leishmaniasis. It is known that the trivalent antimony (SbIII) present as a residue in MA contributes to the drug side effects. In this article, multivariate optimization was used in the synthesis of MA in order to obtain a drug with low levels of SbIII. Four variables (source of antimony, temperature, water volume and pH) were preliminarily evaluated by 24-1 fractional factorial design. Central composite design (CCD) was used to determine the optimal synthesis conditions, using two different sources of SbV and the significant variables selected in a fractional factorial design. Response surface methodology obtained by CCD provided a model with non-significant regression (p = 0.05) for the synthetic route via KSb(OH)6. On the other hand, synthetic route via SbCl5 reached minimum value of SbIII content of 0.172% and significant regression, and it was selected for further evaluations. The analysis of MA formulations synthesized with SbCl5 under optimized conditions revealed the efficiency of multivariate optimization to reduce SbIII content. In addition, the monitoring of some physicochemical parameters of these formulations maintained at 40 ºC for 90 days, showed that stability was not altered at 95% confidence level.

Atomic Spectrometry Update: review of advances in elemental speciation

“…For the speciation of Sb in injectable leishmanicidal drugs by selective HG AAS the signal from Sb V was suppressed by reaction with the citric acid. 30 Previously reported problems of decreasing sensitivity (due to suppression of active sites on the interior to the heated quartz tube walls) and memory effects, were eliminated by careful control of the citric acid concentration, which was substantially decreased compared with those typically recommended by other researchers. Values for the various operating parameters were selected on the basis of a multivariate optimisation consisting of a factorial design followed by a central composite design.…”

Atomic spectrometry update: review of advances in the analysis of metals, chemicals and materials

“…The speciation of Sb in injectable leishmanicidal drugs using hydride generation (HG)-AAS was reported by Fabrino et al 72 Total Sb was determined by reducing the Sb V to Sb III using 0.1 M hydrochloric acid and potassium iodide. Then, HG-AAS analysis took place using hydrochloric acid and a mixture of sodium tetrahydroborate in sodium hydroxide.…”