Department of Chemistry and Biochemistry, University of Oklahoma, Norman, OK 73019, USA.
J Chromatogr A. 2010 Oct 8;1217(41):6413-21. doi: 10.1016/j.chroma.2010.08.016. Epub 2010 Aug 13.
In order to increase productivity of drug analysis in the pharmaceutical industry, an efficient and sensitive generic static headspace gas chromatography (HSGC) method was successfully developed and validated for the determination of 44 classes 2 and 3 solvents of International Conference of Harmonization (ICH) guideline Q3C, as residual solvents in drug substance. In order to increase the method sensitivity and efficiency in sample equilibration, dimethylsulfoxide (DMSO) was selected as the sample diluent based on its high capacity of dissolving drug substance, stability and high boiling point. The HS sample equilibration temperature and equilibration time are assessed in ranges of 125-150°C and 8-15 min, respectively. The results indicate that the residual solvents in 200mg of drug substance can be equilibrated efficiently in HS sampler at 140°C for 10 min. The GC parameters, e.g. sample split ratio, carrier flow rate and oven temperature gradient are manipulated to enhance the method sensitivity and separation efficiency. The two-stage gradient GC run from 35 to 240°C, using an Agilent DB-624 capillary column (30 m long, 0.32 mm I.D., 1.8 μm film thickness), is suitable to determine 44 ICH classes 2 and 3 solvents in 30 min. The method validation results indicate that the method is accurate, precise, linear and sensitive for solvents assessed. The recoveries of most of these solvents from four drug substances are greater than 80% within the method determination ranges. However, this method is not suitable for the 10 remaining ICH classes 2 and 3 solvents, because they are too polar (e.g. formic acid and acidic acid), or have boiling points higher than 150°C, (e.g. anisol and cumene). In comparison with the previous published methods, this method has a much shorter sample equilibration time, a better separation for many solvents, a higher sensitivity and a broader concentration range.
为了提高制药行业药物分析的生产力，我们成功开发并验证了一种高效、灵敏的通用静态顶空气相色谱（HSGC）方法，用于测定国际协调会议（ICH）指南 Q3C 中 44 类 2 类和 3 类溶剂，作为原料药中的残留溶剂。为了提高方法在样品平衡时的灵敏度和效率，选择二甲基亚砜（DMSO）作为样品稀释剂，因为它具有溶解药物物质的高能力、稳定性和高沸点。HS 样品平衡温度和平衡时间分别评估在 125-150°C 和 8-15 min 的范围内。结果表明，在 140°C 下 10 min 内可以有效地平衡 200mg 药物物质中的残留溶剂。GC 参数，例如样品分流比、载气流速和柱箱温度梯度，被操纵以提高方法的灵敏度和分离效率。使用 Agilent DB-624 毛细管柱（30 m 长，0.32 mm ID，1.8 μm 膜厚）进行两阶段梯度 GC 运行，从 35°C 到 240°C，适用于在 30 min 内测定 44 种 ICH 2 类和 3 类溶剂。方法验证结果表明，该方法对评估的溶剂准确、精密、线性和灵敏。这些溶剂中大多数从四种药物物质中的回收率在方法测定范围内大于 80%。然而，这种方法不适合其余的 10 种 ICH 2 类和 3 类溶剂，因为它们太极性（例如甲酸和酸性酸），或者沸点高于 150°C（例如茴香脑和异丙苯）。与以前发表的方法相比，该方法具有更短的样品平衡时间、对许多溶剂更好的分离、更高的灵敏度和更宽的浓度范围。
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