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

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.

葡甲胺锑酸盐（Meglumine antimoniate, MA）是一类推荐用于治疗利什曼病的五价锑（SbV）类药物。已知MA中以残留形式存在的三价锑（SbIII）是引发该药物不良反应的关键因素。本文采用多变量优化策略开展MA的合成研究，以制备三价锑残留水平较低的目标药物。
研究首先通过24-1部分因子设计，对4个变量（锑源、反应温度、加水量及pH值）进行初步筛选。随后采用中心复合设计（Central composite design, CCD），结合两种不同的五价锑源与部分因子实验筛选出的显著变量，确定最优合成条件。
通过中心复合设计得到的响应面法分析结果显示，以六羟基合锑酸钾（KSb(OH)6）为原料的合成路线，其回归模型无统计学显著性（p=0.05）。而以五氯化锑（SbCl5）为原料的合成路线可实现最低0.172%的三价锑残留量，且回归模型具有统计学显著性，因此被选为后续验证的合成路径。
对以五氯化锑为原料、在优化条件下合成的MA制剂进行分析，结果证实多变量优化策略可有效降低三价锑残留含量。此外，对该类制剂在40℃条件下放置90天的部分理化参数进行监测，结果表明在95%置信水平下，其稳定性未发生显著变化。