Laboratory for Pharmaceutical Analysis, Faculty of Pharmaceutical Sciences, Katholieke Universiteit Leuven, O & N 2, Herestraat 49 (PB 923), B-3000 Leuven, Belgium.
J Pharm Biomed Anal. 2011 Jul 15;55(5):1017-23. doi: 10.1016/j.jpba.2011.04.004. Epub 2011 Apr 12.
Residual solvents are volatile organic compounds which can be present in pharmaceutical substances. A generic static headspace-gas chromatography analysis method for the identification and control of residual solvents is described in the European Pharmacopoeia. Although this method is proved to be suitable for the majority of samples and residual solvents, the method may lack sensitivity for high boiling point residual solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and benzyl alcohol. In this study, liquid paraffin was investigated as new dilution medium for the analysis of these residual solvents. The headspace-gas chromatography method was developed and optimized taking the official Pharmacopoeia method as a starting point. The optimized method was validated according to ICH criteria. It was found that the detection limits were below 1μg/vial for each compound, indicating a drastically increased sensitivity compared to the Pharmacopoeia method, which failed to detect the compounds at their respective limit concentrations. Linearity was evaluated based on the R(2) values, which were above 0.997 for all compounds, and inspection of residual plots. Instrument and method precision were examined by calculating the relative standard deviations (RSD) of repeated analyses within the linearity and accuracy experiments, respectively. It was found that all RSD values were below 10%. Accuracy was checked by a recovery experiment at three different levels. Mean recovery values were all in the range 95-105%. Finally, the optimized method was applied to residual DMSO analysis in four different Kollicoat(®) sample batches.
残留溶剂是可能存在于药物物质中的挥发性有机化合物。欧洲药典中描述了一种用于识别和控制残留溶剂的通用静态顶空-气相色谱分析方法。尽管该方法已被证明适用于大多数样品和残留溶剂，但对于沸点较高的残留溶剂，如 N，N-二甲基甲酰胺、N，N-二甲基乙酰胺、二甲基亚砜和苯甲醇，该方法可能缺乏灵敏度。在本研究中，液体石蜡被用作分析这些残留溶剂的新稀释剂。以官方药典方法为起点，开发并优化了顶空-气相色谱法。根据 ICH 标准对优化后的方法进行了验证。结果发现，每种化合物的检测限均低于 1μg/小瓶，与药典方法相比灵敏度显著提高，药典方法未能在各自的限度浓度下检测到这些化合物。基于 R(2) 值评估了线性度，所有化合物的 R(2) 值均高于 0.997，并且检查了残差图。通过计算在线性和准确度实验中重复分析的相对标准偏差（RSD），分别检查了仪器和方法的精密度。结果发现，所有 RSD 值均低于 10%。通过在三个不同水平进行回收实验检查了准确度。平均回收率值均在 95-105%范围内。最后，将优化后的方法应用于四个不同 Kollicoat(®) 样品批次中残留 DMSO 的分析。
